Formation of ibrutinib solvates: so similar, yet so different

The transformation processes of non-solvated ibrutinib into a series of halogenated benzene solvates are explored in detail here. The transformation was studied in real time by X-ray powder diffraction in a glass capillary. Crystal structures of chloro­benzene, bromo­benzene and iodo­benzene solvates are isostructural, whereas the structure of fluoro­benzene solvate is different. Four different mechanisms for transformation were discovered despite the similarity in the chemical nature of the solvents and crystal structures of the solvates formed. These mechanisms include direct transformations and transformations with either a crystalline or an amorphous intermediate phase. The binding preference of each solvate in the crystal structure of the solvates was examined in competitive slurry experiments and further confirmed by interaction strength calculations. Overall, the presented system and online X-ray powder diffraction measurement provide unique insights into the formation of solvates.

1. Introduction

Multicomponent crystals, i.e. salts, cocrystals and solvates, have been actively researched for several decades in academia as well as in industry. Academic researchers discovered new multicomponent crystals and have studied the intermolecular interactions within the crystal structures. The arrangement of molecules in crystal structures determines the crystal properties (Aguiar & Zelmer, 1969; Matsuda et al., 2011; Zvoníček et al., 2018; Sun & Grant, 2001; Kokubo et al., 1987; Pandit et al., 1984). Therefore, approaches that can shed new light on molecular interactions within these crystals and their properties have received a lot of attention in recent years. These include both computational and experimental efforts, such as structure–property relations (Suresh et al., 2015; Stanton & Bak, 2008; de Moraes et al., 2017; Arlin et al., 2011; Collier et al., 2006), crystal structure prediction (Price, 2014; Reilly et al., 2016), intermolecular energy calculations and other types of calculations (Dash & Thakur, 2021; Musumeci et al., 2011; Issa et al., 2009; Karamertzanis et al., 2009), or systematic screening and rational design of multicomponent crystals with desired properties (Aakeröy & Salmon, 2005; Sládková et al., 2015; Desiraju, 1995; Amrutha et al., 2020). Various industrial fields also contribute to the fast development of multicomponent crystals. Improvement of physical properties of high-value chemical products has been demonstrated for agrochemicals (Nauha & Nissinen, 2011), solid explosives (Bolton et al., 2012) and in particular for pharmaceuticals (Zvoníček et al., 2017; Billot et al., 2013; Stanton & Bak, 2008; Schultheiss & Newman, 2009).

Tens of thousands of new multicomponent crystals were discovered since the first reported organic:organic cocrystal (quinhydrone) back in 1884 by Wöhler (1844). The majority of their crystal structures were solved over time [the crystal structure of quinhydrone was solved in 1958, long after its discovery (Matsuda et al., 1958)]. Chemical and physical properties of new multicomponent crystals are routinely characterized during the screening process in both academia and industry, thus quickly epanding the knowledge and applicability of multicomponent solids.

Despite fast progress in the crystal engineering field and the ever-growing datasets, the process of multicomponent crystal formation itself remains inadequately understood. Commonly used methods for characterization of crystalline materials, such as powder X-ray diffraction (PXRD), single-crystal X-ray diffraction (SCXRD), infrared or Raman spectroscopy struggle to capture the formation and transformation of multicomponent crystals. The amount of solvent used during the crystal formation processes poses an obstacle for the sensitivity of these measurement methods. In addition, the design of some devices does not allow for online measurement methods. Furthermore, in cases of fast formation/transformation processes it can be difficult to obtain data with sufficient resolution to interpret the results. A flow-through glass capillary for X-ray measurements was recently introduced (Rohlíček et al., 2020) to overcome some of the above mentioned limitations. The main advantage of this setup is that the transformation period can be captured by methods commonly used to characterize crystalline samples, such as X-ray diffraction. In this work, the flow-through capillary was used to study the process of transformation of the pharmaceutical ingredient ibrutinib (FDA, 2018; Rozovski et al., 2014; Young & Staudt, 2014; Puig de la Bellacasa et al., 2014; Veeraraghavan et al., 2015) into solvates with a series of halogenated benzenes (Fig. 1) [fluoro­benzene (FBZ), chloro­benzene (CBZ), bromo­benzene (BBZ) and iodo­benzene (IBZ)]. This series was explored due to the similarity in chemical nature of the guest molecules and their ability to form multicomponent crystal solvates.

Figure 1 Molecules of ibrutinib and the solvents used (FBZ, CBZ, BBZ and IBZ).

2. Methods and materials

The non-solvated form of Ibrutinib C (Zvoníček et al., 2017, 2018; Purro & David, 2013) was provided by Zentiva k.s. and used as a starting material in all experiments performed. Solvents were obtained from various suppliers and used as received.

2.1. Single-crystal X-ray diffraction

SCXRD of BBZ and IBZ ibrutinib solvates was performed at 95 K using a SuperNova diffractometer with a micro-focus sealed tube, mirror-collimated Cu Kα radiation (λ = 1.54184 Å) and CCD detector Atlas S2. The X-ray diffraction measurements of the structures of apremilast with phthalic acid and o-xylene were carried out at 120 K on an Xcalibur, Gemini ultra diffractometer using Cu Kα radiation (λ = 1.54178 Å) from a fine-focus sealed X-ray tube with a graphite monochromator and CCD detector Atlas S2.

The data reduction and absorption correction were carried out using the CrysAlisPro software (Rigaku Oxford Diffraction, 2019). The structure was solved by charge-flipping methods using the Superflip software (Palatinus & Chapuis, 2007) and refined by full matrix least squares on the F squared value using the Crystals software (Betteridge et al., 2003). MCE software (Rohlíček & Hušák, 2007) was used for visualization of residual electron density maps. According to common practice, the hydrogen atoms attached to carbon atoms were placed geometrically with U_iso(H) in the range 1.2–1.5 U_eq of the parent atom (C). The structures have been deposited in the Cambridge Structural Database (CCDC nos. 2166306, 2166307 and 2164831).

2.2. Powder X-ray diffraction

Diffraction patterns of the sample in the flow-through capillary were collected with the powder diffractometer device Empyrean of PANalytical, with a Cu Kα X-ray beam (λ = 1.542 Å, focusing mirror, voltage: 45 kV, current: 40 mA). The fast scans were measured in the range 5–9° 2θ with a step size of 0.013° 2θ and an overall measurement time of 5 min. The measurement for the structure determination was performed on a flat sample at 3–80° 2θ with a step size of 0.013° 2θ and an overall measurement time of 20 h.

The diffraction patterns of resulting solid samples from competitive slurries were collected with the Bruker AXS D8 powder diffractometer, a Cu Kα X-ray beam (λ = 1.7903 Å), 5–40° 2θ measured range, 34 kV excitation voltage, 30 mA anodic current and 0.0196° 2θ step size. The measurement was performed on a flat sample with an area/thickness ratio equal to 10/0.5 mm. The HighScore Plus (Degen et al., 2014) software was used to process the diffraction patterns.

2.3. Differential scanning calorimetry

Samples for differential scanning calorimetry (DSC) measurements were weighed in an aluminium pan (5–10 mg). The pan was covered and the measurement was carried out under a nitro­gen gas flow of 50 ml min⁻¹. All the measurements were performed on the DSC 822^e, Mettler Toledo instrument. The range of investigated temperatures was 0 to 300°C at a heating rate of 10°C min⁻¹ (amplitude = 0.8°C, period = 60 s).

2.4. Thermogravimetric analysis

Thermogravimetric analysis (TGA) was performed on a TG 209, Netzsch instrument. Approximately 10 mg of the sample was weighed into a ceramic pan and measured under a nitro­gen atmosphere. The TGA measurement was performed in the approximate temperature range 20–300°C. A heating rate of 10°C min⁻¹ was used in all experiments.

2.5. Raman spectroscopy

Samples for Raman spectroscopy were measured in HPLC glass vials in an FT-Raman RFS100/S spectrometer device with a germanium detector (Bruker Optics, Germany). The wavelength of the Nd:YAG laser was 1064 nm. The measurement range was 4000 to 0 cm⁻¹, with a spectral resolution of 4.0 cm⁻¹. Data were obtained at either 64 or 128 accumulations of the measured spectra. The software OPUS and OMNIC were used to process the Raman spectra.

2.6. Competitive slurry

All combinations of solvents were mixed in equimolar ratios in HPLC vials. Approximately 150 µl of each solvent was used. A mass of 100 mg of ibrutinib C was subsequently mixed with all possible combinations of the solvents. Vials were placed in a ThermoMixer C shaker at room temperature and mixed at 600 rev min⁻¹. Vials were slurried for 48 h. The slurry was filtered and dried for 24 h at 40°C and 150 mbar. The prepared samples were analyzed using PXRD to confirm solvate structure formation and NMR to determine the ratio of solvents in the solid samples.

2.7. Nuclear magnetic resonance

Nuclear magnetic resonance (NMR) spectra were obtained using a Bruker Advance 500 (Bruker Biospin, Germany) at 500.13 MHz with a 5 mm Prodigy probe. Liquid NMR experiments were performed in di­methyl­sulfoxide or deuterated. The measurement temperature was 298 K.

2.8. Interaction energy calculations

Several approaches were chosen to estimate the interaction energy within the crystal structures. Solved solvate structures and ibrutinib polymorph C were optimized in the CASTEP program (Clark et al., 2005). Final enthalpies of all optimized structures were then used to obtain the interaction energies of the solvates: E_int = E_solvate − (E_ibrutinib + E_solvent). A different approach was based on isolated molecules and unit cells using the Gaussian16 software (Frisch, et al., 2016). The interaction energy was obtained with 2E_int = E_solvate − (E_ibrutinib + E_solvent). Finally, crystal elongation energies were estimated using structures containing optimized unit cells in different directions (i.e. 2 × 1 × 1, 1 × 2 × 1, 1 × 1 × 2). Crystal elongation energies in each direction were established according to the formula E_elongation = E_{2 × 1 × 1} − 2E_{1 × 1 × 1}.

3. Results and discussion

The ibrutinib solvates used to explore solid-state transformations were firstly characterized from a crystallographic point of view. The mechanism and kinetics of the transformations were studied using X-ray diffraction and complemented by thermodynamic experiments. Furthermore, the interaction energies of the crystal structures were calculated and compared with the experimental results.

3.1. Crystallography

To obtain insight into the crystal packing and intermolecular interactions, single crystals of all solvates were analyzed by SCXRD and their structures were solved. Crystal structures of the CBZ and FBZ solvates have been already reported in the literature as well as their comprehensive crystallographic analyses (Zvoníček et al., 2017; Vasilopoulos et al., 2022; Rohlíček et al., 2020). The packing similarities of the solvate crystal structures were explored using CrystalCMP (Rohlíček et al., 2016) and further crystallographic details of the structures are listed in the supporting information.

All four solvates crystallize in the triclinic system in the space group P1, with two molecules of ibrutinib and two molecules of the respective solvent in the unit cell. When compared from the point of view of molecular packing and unit-cell parameters, three of the solvates are isostructural (CBZ, BBZ and IBZ) and one is different (FBZ). The unit cells of the isostructural solvates (CBZ, BBZ and IBZ) contain two molecules of ibrutinib and two molecules of the respective solvent. Their cell parameters are very similar: a ≃ 11 Å, b ≃ 12 Å, c ≃ 12 Å, α ≃ 80°, β ≃ 69°, γ ≃ 69°. The unit-cell parameters of the FBZ solvate are a ≃ 9.6 Å, b ≃ 11.1 Å, c ≃ 14.2 Å, α ≃ 73.2°, β ≃ 82.1°, γ ≃ 66.0°. Fig. 2(a) shows the overlay of the conformations of ibrutinib and the positions of the solvent molecule. The FBZ solvate crystal structure differs due to the rotation of the outer parts of the ibrutinib molecule. FBZ also occupies a different spot in the FBZ solvate structure compared with the other solvents.

Figure 2 (a) Comparison of the solvate crystal structures (red – FBZ solvate, green – CBZ solvate, blue – BBZ solvate, orange – IBZ solvate). (b) Packing similarity dendrogram generated by CrystalCMP.

Fig. 2(b) shows the molecular packing similarity tree diagram calculated by CrystalCMP. It indicates that the molecular packing of ibrutinib molecules is almost identical in the three isostructural solvates. CBZ, BBZ and IBZ form isostructural cavity solvates with ibrutinib, whereas FBZ forms a channel solvate (see Fig. S4 of the supporting information).

3.2. Mechanism and kinetics of transformation

The transformations from ibrutinib C to halogen benzene solvates were studied using a flow-through capillary. We filled the glass capillary with ibrutinib C and mounted it in the PXRD device. We then initiated the measurement sequence of PXRD patterns, and the solvent was pumped through the glass capillary. Polymorph C of ibrutinib transformed into the solvated form following contact of the solid and liquid phases. We obtained a time series of diffraction patterns to monitor the phase transition. Fig. 3(a) depicts a scheme of the glass capillary.

Figure 3 (a) Scheme of the glass flow-through capillary. (b) Diffraction patterns of ibrutinib polymorph C and of the prepared ibrutinib solvates. (c) Time series of diffraction patterns observed during the transformation of ibrutinib C to the FBZ solvate.

Due to isostructural crystal packing, there is a certain degree of similarity in the diffraction patterns of CBZ, BBZ and IBZ solvates [see Fig. 3(b)]. However, the diffraction patterns of ibrutinib C and the ibrutinib solvates are significantly different between 5 and 9° [Fig. 3(a)]. The fact that each form has well defined, intensive peaks (at approximately 6.4° for the FBZ solvate and 7° for ibrutinib C) in this region helps to easily distinguish their diffraction patterns. The diffraction patterns of the CBZ, BBZ and IBZ solvates in this region also exhibit two characteristic peaks at approximately 8°. Therefore, we conveniently selected the region of 5–9° to monitor the transformations in all experiments performed. A certain degree of similarity in the diffraction patterns of CBZ, BBZ and IBZ can be observed owing to isostructural crystal packing. Fig. 3(c) shows the time evolution of the diffraction patterns after filling the flow-through capillary with FBZ. The changes in diffraction patterns reflect the transformation of non-solvated polymorph C to the FBZ solvate. Only ibrutinib C is present in the sample at the start of the measurement (the only peak present is at 7°). The gradual transformation of the sample is reflected by the extinction of the ibrutinib peak at ∼7° and progressive evolution of the FBZ solvate peak at 6.4°. The sample underwent full transformation to the FBZ solvate after complete extinction of the ibrutinib C peak at 7°. This entire transformation process takes approximately 130 s. We can describe the FBZ transformation as a direct (without any intermediate phases) and fast transformation that results in a channel solvate structure

A larger range (5–30°) was measured only before and after completion of the transformation. We measured only several degrees (5–9°) to minimize the required measurement time, which allows more frequent measurements during the transformation and therefore results in more accurate observation of the transformation process. Nevertheless, an optimal balance needs to be found between the quality of the measured data and the time required for the measurement. The transformation of ibrutinib C to the FBZ solvate was measured at 10 s intervals. In some cases, the 10 s time resolution between measurements was too low. Therefore, the diffraction patterns were then measured every 3 s, which resulted in more frequent, but also noisy data. Measuring the entire diffraction pattern would not provide any useful information, because the transformation would finish much faster than the measurement of a single diffraction pattern. However, the entire diffraction pattern was measured before and after the transformation process to confirm the complete transformation of the sample.

We performed the same procedure and evaluation for the three remaining solvents. The time evolution of the diffraction patterns for all four transformations is shown in Fig. 4. The observed noise in a number of the diffraction patterns can be attributed to the very short measurement time required to capture the fast transformation. It is interesting that the time evolution of diffraction patterns is different for each of the transformations, despite the similarity in chemical nature of the solvents and the similarity in the crystal packing (with the exception of the FBZ solvate).

Figure 4 Transformation of ibrutinib form C to all four solvates illustrated by the evolution of diffraction patterns.

As discussed above, the FBZ solvate transformation is fast (approximately 130 s) and direct. In contrast, the transformation of ibrutinib C to the CBZ solvate is more complex as indicated by the PXRD measurement of the transformation. A new peak at 6.5° appears in the diffraction patterns during the CBZ solvate transformation. This peak (marked by a gray circle in Fig. 4) does not correspond to ibrutinib C, or any other ibrutinib polymorph, nor the CBZ solvate. This indicates the formation of a new crystalline phase during the transformation period. The low-intensity and rapid extinction of the peak once we filled the capillary with CBZ led us to the conclusion that an intermediate crystalline form has a vital role in the formation of the CBZ solvate. This peak formed and was consistently present in experiments where only half of the capillary was filled with CBZ (PXRD measured both dry ibrutinib, wet ibrutinib and the interface between the two). Therefore, we assumed that the new intermediate phase forms at the interface of the solvated and non-solvated sample. After the interface is supplied with more solvent, the intermediate phase transforms into the CBZ solvate structure and the peak at 6.5° is no longer present. We successfully isolated the intermediate phase with further experiments (a detailed description is provided in the supporting information) and measured its diffraction pattern, which confirms the formation of the intermediate crystalline phase during the CBZ solvent transformation (Fig. 5).

Figure 5 Measured diffraction patterns of the empty capillary (ibrutinib form C), half-filled capillary (ibrutinib form C + CBZ solvate + intermediate crystalline phase), full capillary (CBZ solvate) and intermediate crystalline phase.

The peak with low intensity at 6.5° in the half-filled capillary experiment corresponds well to the peak at 6.5° of the intermediate crystalline phase (highlighted by the gray area in Fig. 5). Only a very small amount of the intermediate phase is present in the half-filled capillary experiment, located at the interface of the solvated and non-solvated samples. This causes very low intensity of the peak, since the interface is only a small part of the measured area. The intermediate crystalline phase was further studied, and its crystal structure was successfully solved from PXRD data (CCDC no. 2164831). We discovered that the intermediate phase contains only one molecule of CBZ and two molecules of ibrutinib in the asymmetric unit. It is a CBZ hemisolvate with unit-cell parameters of a ≃ 14.0 Å, b ≃ 10.2 Å, c ≃ 10.4 Å, α ≃ 116.4°, β ≃ 85.6°, γ ≃ 79.3°, and the space group of the hemisolvate was determined to be P1.

This is in line with the assumption of the intermediate phase formation at the interface. A hemisolvate is formed at the interface, where there is an insufficient amount of CBZ molecules. After additional CBZ is supplied, the transformation continues further from the CBZ hemisolvate form to the final CBZ solvate (1:1) form.

Overall, the transformation of the CBZ solvate is more complex than in the case of the FBZ solvate. It is a fast transformation with a crystalline intermediate phase, where the first step is the transformation of ibrutinib C to the crystalline intermediate CBZ hemisolvate, which in a very short time can transform further into the CBZ (1:1) solvate after additional supply of CBZ.

The BBZ solvate transformation is much simpler (see Fig. 4). It is a fast and direct transformation, as in the case of the FBZ transformation. Nevertheless, the difference between the BBZ and FBZ transformations is in their final forms. The BBZ solvate is a cavity solvate with a different crystal structure compared with the FBZ channel solvate.

The mechanism of the IBZ solvate transformation is vastly different compared with the rest of the solvates. The sample becomes amorphous after the ibrutinib C makes contact with IBZ. This is confirmed by the diffraction patterns with no peaks. As long as the sample was in contact with the solvent, it remained amorphous. Visual inspection confirmed that the sample had not dissolved. The peaks in the diffraction pattern of the IBZ solvate began to evolve after the sample started to dry out and the excess IBZ evaporated. The evolution of the peaks, and the transformation itself, progressed continuously as the sample dried. The sample completely transformed after all the excess solvent evaporated. The sample changes to the amorphous form instantly on contact with the solvent. Therefore, the rate of transformation is entirely dependent on the slower phenomenon, the rate of drying.

Thus, we observed four different mechanisms of the transformation: FBZ – fast and direct transformation to the channel solvate structure, CBZ – fast transformation with a crystalline intermediate phase resulting in the cavity solvate structure, BBZ – fast and direct transformation to the cavity solvate structure, IBZ – fast transformation with an amorphous intermediate phase resulting in the cavity solvate structure. We compared experimental diffraction patterns of the samples after transformation with patterns generated from obtained crystal structures to ensure the consistency of the transformation process (Fig. S2).

3.3. Thermodynamics

We investigated the thermodynamic preference of the solvate structure formation to complement the results of the solvate transformations. For this purpose, we performed competitive slurry experiments. First, we created all possible pairs of our solvents and mixed them in the same molar ratios. Thus, as an example, a binary mixture of FBZ and CBZ in the molar ratio 1:1 was prepared. Analogously, all possible triplets and quartets of FBZ, CBZ, BBZ and IBZ were mixed in equimolar ratios. All prepared combinations of two, three and four solvents were slurred with ibrutinib C. Solvate structure formation was confirmed by PXRD and the content of each solvent in the solid sample was examined by liquid nuclear magnetic resonance spectroscopy (¹H NMR). Table 1 lists the solvent contents in the solid samples for all competitive slurry experiments. We expected that the strongest-binding solvent in the solvate structures would be the most abundant in the final solvate sample. For example, a binary mixture of IBZ and FBZ (sample J in Table 1) contains almost exclusively IBZ solvent in the resulting solvate structure. This suggests stronger interactions of IBZ molecules in the solvate structure compared with FBZ molecules.

Table 1
Solvent content in slurry experiments (A: 4 solvents, B–E: 3 solvents, F–K: 2 solvents) as estimated by ^lH NMR

	Solvent
Ibrutinib C	FBZ	CBZ	BBZ	IBZ
A	0	0.3	0.33	0.5
B	–	0	0.3	0.5
C	0	–	0.33	0.72
D	0	0.26	–	0.85
E	0	0.33	0.65	–
F	–	–	0.4	0.69
G	–	0.2	–	0.85
H	0.07	–	–	0.9
I	–	0.35	0.75	–
J	0	–	0.98	–
K	0	0.4	–	–

The sum of the analyzed solvent content is not always equal to one, despite following identical experimental procedure. In some cases, it was difficult to accurately evaluate the ^lH NMR spectra, due to many overlapping bands, but the phenomenon of the preferential solvate formation is clear. Different rates of solvent drying from a solid sample may also contribute to the imperfect molar ratio. For instance, sample A is a mixture of all four solvents but the total content is higher than one. The observed ratios from that sample suggest the strongest preference for IBZ, while BBZ and CBZ behave similarly, and FBZ exhibits the lowest preference. We further explored the similarity of CBZ and BBZ in sample I, where in the binary system of the two solvents, BBZ had higher preference compared with CBZ. We observed the same trend of higher preference of BBZ over CBZ in triplet samples B and E. After a complete evaluation of Table 1, we suggest a preference sequence. Ibrutinib has the strongest preference to form the IBZ solvate and the least preferable is the FBZ channel solvate. The sequence of preference is as follows: IBZ > BBZ > CBZ > FBZ. This reflects the strength of interactions between ibrutinib and the respective solvents. We performed a set of DFT-based calculations to shed more light on the deep nature of interactions within the solvate structures which control their formation.

3.4. Calculations

We applied two basic DFT-based approaches to explain the increasing tendency of ibrutinib to form a halogen benzene solvate with increasing halogen atomic number. Both approaches focused on estimations of interaction energies (E_int) of a solvate unit cell associated with the formation of the cell from individual components. For more details, see the Methods in the supporting information. The first approach calculates E_int using the periodic conditions in CASTEP (Clark et al., 2005), whereas the second treats a solvate or its components as isolated systems (i.e. as single unit cells or isolated molecules). To test the sensitivity of E_int (or trends in E_int) to structural parameters of a solvent, we tested two modifications of the CASTEP approach. One variation [labeled CASTEP(2)] used the chosen unit cell of the solvent containing two molecules of solvent. In the second variation [labeled CASTEP(1)] we placed only one molecule of the solvent in the unit cell. The unit cell for a solvent was arbitrarily created from the corresponding solvate unit cell as described in the Methods. Fig. 6(a) graphically summarizes E_int estimated by all three methods. Table S2 of the supporting information then shows individual values. In general, a lower E_int means a stronger interaction among moieties in a solvate and hence the higher preference for its formation. We can see that all approaches reproduced the trend of increased preference of formation effectively (i.e. FBZ < CBZ < BBZ < IBZ) as the energy increased in the same series. Nevertheless, neglecting environmental effects in the isolated system approach is obviously too crude, as it estimated a positive E_int for FBZ and CBZ. This would suggest that they will not form, which does not agree with the experiment. Both CASTEP approaches correctly estimated negative E_int values for all solvates with increasing absolute values in the FBZ < CBZ < BBZ < IBZ series (Fig. 7). The CASTEP(1) approach provides a larger E_int by about ∼5.2 kcal mol⁻¹. The decrease of absolute values in the CASTEP(2) approach can be attributed to the mutual interaction of two solvent molecules in the optimized unit cell. This leads to the lower energy of the solvent that results in slightly higher E_int. Nevertheless, we cannot decide whether the mutual interaction of solvent molecules in pure solvent (according to our model) is not excessive. Therefore, our predictions have a more qualitative than quantitative value. Similarly, we also estimated E_int of the CBZ intermediate. Fig. 6(b) shows the values relative to the CBZ solvate, clearly showing the formation course: IBR → intermediate → solvate. Optimized parameters of unit cells for all solvates are gathered in Table S3.

Figure 6 Different mechanisms of the transformation for FBZ, CBZ, BBZ and IBZ.

Figure 7 (a) Eint estimated using two CASTEP-based approaches and for the isolated system. (b) Relative Eint for the ibrutinib–CBZ solvate formation.

To identify a possible source of interactions between IBR and solvents, we also calculated E_elongation for all solvates to predict the energy associated with elongation of a crystal in a certain direction. For computational details, see the Methods. Table S4 summarizes E_elongation estimated for all solvates at two theoretical levels. The lower level (PBE/3-21G) provides likely overestimated values, as E_elongation decreases with increased basis set. We can see that elongation in one particular direction applies to all solvents associated with substantially larger E_elongation. This corresponds to elongation in the direction with the highest contribution of parallel-displaced π–π interactions. Different directions with the strongest E_elongation for different solvates can be attributed to different unit-cell orientations. We observe a slight increase of E_elongation in the FBZ < CBZ < BBZ series, which could indicate a slight increase of crystal strength in the same order. Energies for IBZ seem unreliably low due to the low-level of theory or the neglect of relativistic contributions.

Thermal behavior of the solvates is consistent with the results obtained from the competitive slurry experiment and the interaction energy calculations. The melting temperatures of the prepared solvates were evaluated and the IBZ solvate shows the highest melting temperature at 125°C. The melting temperature of the BBZ solvate was 110°C, the CBZ solvate was 96°C and the FBZ solvate was around 99°C. The calculated interaction strength as well as the preferred formation of the IBZ solvate correlate well with its higher thermal stability. The descending melting temperatures of BBZ and CBZ solvates follow equal logic. The FBZ solvate cannot be easily compared with the rest of the solvates since its crystal structure is different. Even though the descending order of melting temperatures cannot be considered direct proof of interaction strength, it provides additional insight and information about the solvate series.

4. Conclusions

The mechanism of solvate structure formation, thermodynamics and calculations form a coherent set of results. The calculated interaction energies of the solvent and ibrutinib molecules agree well with the increasing tendency of ibrutinib to form a halogen benzene solvate with increasing halogen atomic number, determined from competitive slurry experiments. The calculated interaction energy was lowest for the IBZ solvate, followed by the BBZ, CBZ and FBZ solvates which have increasingly higher interaction energies. The preference of solvate formation reflects the interaction energies well as the IBZ solvate forms more easily than the other solvates, followed by BBZ, CBZ and FBZ, which form in lower amounts, respectively, in the presence of other solvents. Further, we propose a hypothesis based on the observed results about how the interaction strength impacts the mechanism of solvate formation. During the formation of the IBZ solvate the sample becomes amorphous on contact with the IBZ solvent. We attribute this phenomenon to the strength of the IBZ and ibrutinib interaction (higher than the other solvates) which disrupts the crystalline structure of ibrutinib in excess IBZ. The crystalline order is restored after evaporation of the excess molecules of solvent and the cavity solvate is formed. In the case of the BBZ solvate, the interaction is weaker, and the mechanism of transformation is direct, without the amorphous intermediate phase. The resulting crystal structure is also the cavity solvate, which is isostructural with the IBZ solvate. The interaction strength of CBZ and ibrutinib is slightly weaker again. The mechanism of the CBZ solvate transformation requires a crystalline intermediate phase (hemi-CBZ solvate) that is more like the channel FBZ solvate, which has the weakest interaction strength. After a supply of additional CBZ the crystal structure transforms to the final cavity CBZ solvate. The FBZ solvate transforms directly, but the FBZ solvate is not isostructural with the rest of the solvates; it forms the channel solvate as opposed to a cavity solvate.

Overall, the system is fully characterized from the crystal structure and mechanism of transformation to the interaction energies and provides deep insight into the formation of ibrutinib solvates.

5. Related literature

The following references are cited in the supporting information: Macrae et al. (2020); Perdew et al. (1996); Grimme (2006); Monkhorst & Pack (1976).

Supporting information

Computing details

Data collection: SuperNova, (Oxford Diffraction, 2010) for bromo, iodo. Cell refinement: CrysAlis PRO, (Agilent, 2011) for bromo, iodo. Data reduction: CrysAlis PRO, (Agilent, 2011) for bromo, iodo. Program(s) used to solve structure: SIR92 (Altomare et al., 1994) for bromo, iodo. Program(s) used to refine structure: CRYSTALS (Betteridge et al., 2003) for bromo, iodo. Molecular graphics: CAMERON (Watkin et al., 1996) for bromo, iodo. Software used to prepare material for publication: CRYSTALS (Betteridge et al., 2003) for bromo, iodo.

(bromo)

Crystal data

C62H58Br2N12O4	Z = 1
Mr = 1195.03	F(000) = 616
Triclinic, P1	Dx = 1.435 Mg m^−3
a = 11.0298 (4) Å	Cu Kα radiation, λ = 1.54180 Å
b = 11.9154 (4) Å	Cell parameters from 11881 reflections
c = 11.9588 (4) Å	θ = 4–71°
α = 80.855 (3)°	µ = 2.35 mm^−1
β = 71.713 (3)°	T = 95 K
γ = 68.106 (3)°	Prism, colorless
V = 1383.10 (5) Å^3	0.37 × 0.12 × 0.08 mm

Data collection

Oxford Diffraction SuperNova diffractometer	9901 reflections with I > 2.0σ(I)
Graphite monochromator	Rint = 0.021
ω scans	θmax = 71.2°, θmin = 3.9°
Absorption correction: multi-scan CrysAlisPro, (Agilent, 2011)	h = −13→12
Tmin = 0.51, Tmax = 0.82	k = −14→14
17859 measured reflections	l = −14→14
9964 independent reflections

Refinement

Refinement on F^2	Hydrogen site location: difference Fourier map
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.034	Method = Modified Sheldrick w = 1/[σ^2(F^2) + ( 0.06P)^2 + 0.97P] , where P = (max(Fo^2,0) + 2Fc^2)/3
wR(F^2) = 0.094	(Δ/σ)max = 0.001
S = 1.00	Δρmax = 0.84 e Å^−3
9964 reflections	Δρmin = −0.66 e Å^−3
734 parameters	Absolute structure: Flack (1983), 4649 Friedel-pairs
11 restraints	Absolute structure parameter: −0.034 (9)
Primary atom site location: structure-invariant direct methods

Special details

Experimental. The crystal was placed in the cold stream of an Oxford Cryosystems open-flow nitrogen cryostat (Cosier & Glazer, 1986) with a nominal stability of 0.1K.

Cosier, J. & Glazer, A.M., 1986. J. Appl. Cryst. 105-107.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
Br1	−0.69574 (5)	−0.86188 (4)	−0.53079 (4)	0.0384
C2	−0.6496 (3)	−0.8385 (3)	−0.3974 (3)	0.0254
C3	−0.5272 (3)	−0.8240 (2)	−0.4152 (3)	0.0276
C4	−0.4891 (3)	−0.8150 (3)	−0.3176 (3)	0.0331
C5	−0.5739 (4)	−0.8190 (3)	−0.2056 (3)	0.0395
C6	−0.6980 (4)	−0.8302 (4)	−0.1906 (3)	0.0484
C7	−0.7385 (3)	−0.8400 (3)	−0.2857 (3)	0.0394
Br8	0.33165 (5)	−1.17960 (5)	−0.95128 (4)	0.0491
C9	0.2852 (3)	−1.1835 (3)	−1.0907 (3)	0.0295
C10	0.1799 (3)	−1.2242 (3)	−1.0802 (3)	0.0324
C11	0.1418 (3)	−1.2237 (3)	−1.1805 (3)	0.0350
C12	0.2090 (3)	−1.1803 (3)	−1.2885 (3)	0.0390
C13	0.3105 (4)	−1.1424 (3)	−1.2968 (3)	0.0429
C14	0.3524 (3)	−1.1425 (3)	−1.1978 (3)	0.0388
O15	−0.5309 (2)	−0.75081 (17)	−0.96581 (19)	0.0266
C16	−0.5555 (3)	−0.6477 (2)	−0.9406 (2)	0.0219
N17	−0.4988 (2)	−0.62367 (19)	−0.8648 (2)	0.0220
C18	−0.5719 (3)	−0.5215 (3)	−0.7873 (3)	0.0270
C19	−0.4745 (3)	−0.4738 (2)	−0.7626 (3)	0.0295
C20	−0.3687 (3)	−0.5762 (2)	−0.7110 (2)	0.0242
C21	−0.2984 (3)	−0.6823 (2)	−0.7924 (2)	0.0196
C22	−0.4013 (3)	−0.7257 (2)	−0.8173 (2)	0.0210
N23	−0.2057 (2)	−0.7829 (2)	−0.7399 (2)	0.0189
N24	−0.2555 (2)	−0.8578 (2)	−0.6537 (2)	0.0205
C25	−0.1524 (3)	−0.9346 (2)	−0.6168 (2)	0.0183
C26	−0.0298 (3)	−0.9110 (2)	−0.6791 (2)	0.0172
C27	−0.0703 (3)	−0.8117 (2)	−0.7555 (2)	0.0189
N28	0.0098 (2)	−0.75447 (19)	−0.83263 (19)	0.0193
C29	0.1369 (3)	−0.8040 (2)	−0.8268 (2)	0.0193
N30	0.1925 (2)	−0.90124 (19)	−0.7623 (2)	0.0202
C31	0.1113 (3)	−0.9609 (2)	−0.6890 (2)	0.0189
N32	0.1727 (2)	−1.0620 (2)	−0.6337 (2)	0.0205
C33	−0.1805 (3)	−1.0210 (2)	−0.5175 (2)	0.0190
C34	−0.1164 (3)	−1.0480 (2)	−0.4282 (2)	0.0212
C35	−0.1531 (3)	−1.1194 (2)	−0.3287 (2)	0.0242
C36	−0.2561 (3)	−1.1634 (2)	−0.3191 (2)	0.0245
O37	−0.3060 (2)	−1.2256 (2)	−0.21751 (19)	0.0349
C38	−0.2161 (3)	−1.3138 (2)	−0.1632 (3)	0.0240
C39	−0.0971 (3)	−1.3962 (3)	−0.2276 (2)	0.0269
C40	−0.0190 (3)	−1.4906 (3)	−0.1679 (3)	0.0305
C41	−0.0587 (3)	−1.5010 (3)	−0.0457 (3)	0.0336
C42	−0.1756 (3)	−1.4158 (3)	0.0165 (3)	0.0336
C43	−0.2549 (3)	−1.3217 (3)	−0.0419 (3)	0.0275
C44	−0.3192 (3)	−1.1398 (2)	−0.4072 (3)	0.0236
C45	−0.2825 (3)	−1.0685 (2)	−0.5061 (2)	0.0201
C46	−0.6422 (3)	−0.5396 (3)	−0.9973 (3)	0.0278
C47	−0.7260 (4)	−0.5504 (3)	−1.0483 (3)	0.0377
O48	0.1818 (2)	−1.30480 (17)	−0.52487 (19)	0.0258
C49	0.1743 (3)	−1.4071 (2)	−0.5089 (2)	0.0207
N50	0.0793 (2)	−1.43393 (18)	−0.53744 (19)	0.0213
C51	−0.0207 (3)	−1.3394 (2)	−0.5886 (2)	0.0240
C52	−0.0180 (3)	−1.3795 (2)	−0.7053 (2)	0.0216
N53	−0.1189 (2)	−1.2841 (2)	−0.7541 (2)	0.0221
N54	−0.0742 (2)	−1.2070 (2)	−0.8412 (2)	0.0213
C55	−0.1829 (3)	−1.1249 (2)	−0.8663 (2)	0.0195
C56	−0.1643 (3)	−1.0273 (2)	−0.9564 (2)	0.0194
C57	−0.0674 (3)	−0.9768 (2)	−0.9569 (2)	0.0218
C58	−0.0465 (3)	−0.8850 (3)	−1.0386 (2)	0.0248
C59	−0.1206 (3)	−0.8427 (2)	−1.1196 (2)	0.0244
O60	−0.0913 (2)	−0.7503 (2)	−1.1956 (2)	0.0373
C61	−0.1776 (3)	−0.6860 (3)	−1.2661 (3)	0.0280
C62	−0.2776 (3)	−0.5775 (3)	−1.2288 (3)	0.0358
C63	−0.3517 (4)	−0.5077 (3)	−1.3052 (3)	0.0404
C64	−0.3265 (3)	−0.5471 (3)	−1.4157 (3)	0.0336
C65	−0.2273 (3)	−0.6582 (3)	−1.4504 (3)	0.0332
C66	−0.1510 (3)	−0.7275 (3)	−1.3755 (3)	0.0316
C67	−0.2155 (3)	−0.8922 (2)	−1.1221 (2)	0.0230
C68	−0.2363 (3)	−0.9853 (2)	−1.0399 (2)	0.0211
C69	−0.3038 (3)	−1.1466 (2)	−0.7941 (2)	0.0185
C70	−0.2567 (3)	−1.2492 (2)	−0.7229 (2)	0.0186
N71	−0.3346 (2)	−1.30204 (19)	−0.6359 (2)	0.0212
C72	−0.4662 (3)	−1.2436 (2)	−0.6269 (2)	0.0208
N73	−0.5258 (2)	−1.14529 (19)	−0.6883 (2)	0.0204
C74	−0.4474 (3)	−1.0917 (2)	−0.7722 (2)	0.0195
N75	−0.5095 (2)	−0.9917 (2)	−0.8268 (2)	0.0214
C76	−0.0378 (3)	−1.5016 (2)	−0.6913 (2)	0.0245
C77	0.0651 (3)	−1.5951 (2)	−0.6312 (2)	0.0225
C78	0.0552 (3)	−1.5496 (2)	−0.5152 (2)	0.0225
C79	0.2733 (3)	−1.5079 (3)	−0.4562 (3)	0.0252
C80	0.3365 (3)	−1.4874 (3)	−0.3907 (3)	0.0322
H31	−0.4679	−0.8229	−0.4916	0.0367*
H41	−0.4033	−0.8052	−0.3286	0.0422*
H51	−0.5476	−0.8152	−0.1397	0.0459*
H61	−0.7562	−0.8319	−0.1151	0.0564*
H71	−0.8230	−0.8483	−0.2761	0.0483*
H101	0.1367	−1.2535	−1.0068	0.0400*
H111	0.0717	−1.2540	−1.1747	0.0428*
H121	0.1822	−1.1789	−1.3548	0.0495*
H131	0.3522	−1.1135	−1.3695	0.0506*
H141	0.4242	−1.1152	−1.2026	0.0492*
H181	−0.6322	−0.4574	−0.8264	0.0338*
H182	−0.6253	−0.5491	−0.7114	0.0343*
H192	−0.4245	−0.4444	−0.8371	0.0373*
H191	−0.5253	−0.4094	−0.7070	0.0366*
H201	−0.4159	−0.6034	−0.6333	0.0324*
H202	−0.3006	−0.5475	−0.7013	0.0322*
H211	−0.2432	−0.6565	−0.8677	0.0241*
H221	−0.3555	−0.7882	−0.8750	0.0268*
H222	−0.4493	−0.7598	−0.7459	0.0269*
H291	0.1972	−0.7633	−0.8756	0.0239*
H341	−0.0459	−1.0157	−0.4353	0.0267*
H351	−0.1103	−1.1378	−0.2679	0.0302*
H391	−0.0705	−1.3880	−0.3101	0.0342*
H401	0.0603	−1.5472	−0.2108	0.0378*
H411	−0.0092	−1.5654	−0.0045	0.0425*
H421	−0.2019	−1.4217	0.1008	0.0411*
H431	−0.3356	−1.2615	0.0003	0.0339*
H441	−0.3877	−1.1727	−0.3993	0.0288*
H451	−0.3256	−1.0527	−0.5652	0.0261*
H461	−0.6379	−0.4618	−0.9946	0.0340*
H471	−0.7299	−0.6269	−1.0520	0.0475*
H472	−0.7838	−0.4802	−1.0796	0.0483*
H511	−0.1116	−1.3252	−0.5339	0.0309*
H512	0.0036	−1.2664	−0.6019	0.0316*
H521	0.0708	−1.3867	−0.7634	0.0271*
H571	−0.0178	−1.0048	−0.8996	0.0284*
H581	0.0187	−0.8496	−1.0383	0.0310*
H621	−0.2936	−0.5529	−1.1528	0.0451*
H631	−0.4189	−0.4332	−1.2822	0.0499*
H641	−0.3767	−0.4980	−1.4684	0.0430*
H651	−0.2108	−0.6857	−1.5250	0.0418*
H661	−0.0824	−0.8029	−1.3966	0.0400*
H671	−0.2648	−0.8623	−1.1775	0.0283*
H681	−0.2990	−1.0202	−1.0432	0.0267*
H721	−0.5263	−1.2771	−0.5693	0.0251*
H761	−0.0222	−1.5299	−0.7683	0.0328*
H762	−0.1307	−1.4932	−0.6424	0.0325*
H772	0.0462	−1.6702	−0.6153	0.0237*
H771	0.1567	−1.6095	−0.6835	0.0252*
H781	0.1213	−1.6104	−0.4785	0.0267*
H782	−0.0366	−1.5347	−0.4622	0.0275*
H791	0.2878	−1.5890	−0.4699	0.0331*
H801	0.3943	−1.5541	−0.3561	0.0394*
H802	0.3237	−1.4064	−0.3774	0.0396*
H752	−0.466 (2)	−0.953 (2)	−0.879 (3)	0.0271*
H322	0.134 (2)	−1.112 (2)	−0.599 (3)	0.0275*
H751	−0.5944 (19)	−0.957 (2)	−0.801 (2)	0.0271*
H321	0.2560 (19)	−1.082 (2)	−0.643 (3)	0.0280*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Br1	0.0485 (2)	0.02661 (14)	0.03474 (17)	0.00400 (13)	−0.02200 (14)	−0.00784 (11)
C2	0.0288 (15)	0.0233 (13)	0.0232 (14)	−0.0017 (11)	−0.0126 (11)	−0.0056 (10)
C3	0.0245 (14)	0.0192 (13)	0.0259 (14)	0.0029 (11)	−0.0021 (11)	−0.0003 (10)
C4	0.0235 (15)	0.0313 (16)	0.0427 (19)	−0.0086 (12)	−0.0068 (13)	−0.0034 (13)
C5	0.0394 (19)	0.051 (2)	0.0324 (17)	−0.0184 (16)	−0.0093 (14)	−0.0086 (14)
C6	0.045 (2)	0.081 (3)	0.0256 (16)	−0.037 (2)	0.0064 (14)	−0.0155 (17)
C7	0.0309 (17)	0.053 (2)	0.0362 (17)	−0.0210 (15)	0.0027 (13)	−0.0152 (15)
Br8	0.0428 (2)	0.0607 (2)	0.03903 (19)	−0.00337 (17)	−0.01585 (15)	−0.01604 (17)
C9	0.0268 (15)	0.0317 (15)	0.0263 (15)	0.0011 (12)	−0.0114 (12)	−0.0104 (12)
C10	0.0262 (15)	0.0265 (14)	0.0325 (15)	−0.0001 (12)	−0.0034 (12)	−0.0004 (12)
C11	0.0261 (16)	0.0257 (15)	0.049 (2)	−0.0001 (12)	−0.0145 (14)	−0.0028 (13)
C12	0.0333 (18)	0.0419 (18)	0.0259 (15)	0.0123 (14)	−0.0147 (13)	−0.0072 (13)
C13	0.050 (2)	0.0381 (17)	0.0252 (15)	−0.0061 (15)	−0.0007 (14)	−0.0004 (13)
C14	0.0283 (16)	0.0412 (18)	0.0417 (18)	−0.0083 (13)	−0.0043 (13)	−0.0081 (14)
O15	0.0298 (11)	0.0202 (10)	0.0312 (11)	−0.0048 (8)	−0.0159 (9)	0.0009 (8)
C16	0.0186 (12)	0.0224 (12)	0.0210 (12)	−0.0035 (10)	−0.0063 (10)	0.0020 (10)
N17	0.0192 (11)	0.0190 (10)	0.0254 (11)	0.0002 (8)	−0.0106 (9)	−0.0024 (8)
C18	0.0204 (13)	0.0249 (13)	0.0309 (14)	0.0024 (11)	−0.0100 (11)	−0.0075 (11)
C19	0.0275 (15)	0.0190 (12)	0.0395 (16)	0.0016 (11)	−0.0150 (12)	−0.0070 (11)
C20	0.0232 (13)	0.0214 (12)	0.0275 (13)	−0.0035 (10)	−0.0107 (11)	−0.0023 (10)
C21	0.0158 (12)	0.0198 (12)	0.0189 (12)	−0.0025 (10)	−0.0060 (10)	0.0044 (9)
C22	0.0205 (13)	0.0174 (11)	0.0209 (12)	−0.0022 (10)	−0.0066 (10)	0.0015 (9)
N23	0.0152 (11)	0.0188 (10)	0.0186 (10)	−0.0029 (8)	−0.0058 (8)	0.0051 (8)
N24	0.0190 (11)	0.0215 (11)	0.0168 (10)	−0.0051 (9)	−0.0034 (8)	0.0031 (8)
C25	0.0145 (12)	0.0174 (11)	0.0197 (12)	−0.0010 (9)	−0.0061 (10)	0.0000 (9)
C26	0.0189 (13)	0.0152 (11)	0.0150 (11)	−0.0046 (9)	−0.0039 (9)	0.0016 (9)
C27	0.0153 (12)	0.0189 (11)	0.0186 (12)	−0.0013 (10)	−0.0047 (10)	−0.0017 (9)
N28	0.0197 (11)	0.0189 (10)	0.0166 (10)	−0.0045 (9)	−0.0051 (8)	0.0015 (8)
C29	0.0191 (13)	0.0183 (11)	0.0175 (12)	−0.0044 (10)	−0.0043 (10)	0.0008 (9)
N30	0.0175 (10)	0.0169 (10)	0.0230 (11)	−0.0036 (8)	−0.0046 (8)	0.0001 (8)
C31	0.0196 (13)	0.0156 (11)	0.0180 (12)	−0.0035 (10)	−0.0031 (10)	−0.0018 (9)
N32	0.0154 (11)	0.0176 (10)	0.0246 (11)	−0.0033 (8)	−0.0057 (9)	0.0040 (8)
C33	0.0163 (12)	0.0148 (11)	0.0194 (12)	−0.0016 (9)	−0.0015 (10)	0.0006 (9)
C34	0.0194 (13)	0.0175 (11)	0.0206 (13)	−0.0004 (9)	−0.0046 (10)	−0.0005 (9)
C35	0.0219 (13)	0.0235 (13)	0.0202 (13)	−0.0012 (10)	−0.0064 (10)	0.0034 (10)
C36	0.0207 (13)	0.0221 (12)	0.0193 (12)	−0.0014 (10)	−0.0006 (10)	0.0059 (10)
O37	0.0228 (10)	0.0413 (12)	0.0281 (10)	−0.0075 (9)	−0.0044 (8)	0.0182 (9)
C38	0.0223 (13)	0.0215 (12)	0.0249 (14)	−0.0071 (10)	−0.0062 (11)	0.0065 (10)
C39	0.0287 (15)	0.0283 (14)	0.0187 (12)	−0.0083 (11)	−0.0023 (11)	0.0008 (10)
C40	0.0260 (15)	0.0261 (14)	0.0325 (15)	−0.0064 (12)	−0.0044 (12)	0.0036 (11)
C41	0.0296 (16)	0.0344 (16)	0.0349 (17)	−0.0091 (13)	−0.0154 (13)	0.0123 (13)
C42	0.0336 (16)	0.0447 (18)	0.0201 (13)	−0.0130 (14)	−0.0097 (12)	0.0090 (12)
C43	0.0263 (14)	0.0265 (13)	0.0251 (14)	−0.0076 (11)	−0.0037 (11)	0.0005 (11)
C44	0.0162 (12)	0.0188 (12)	0.0299 (14)	−0.0041 (10)	−0.0021 (10)	0.0017 (10)
C45	0.0171 (13)	0.0175 (12)	0.0201 (13)	0.0000 (10)	−0.0053 (10)	0.0002 (9)
C46	0.0308 (15)	0.0218 (13)	0.0309 (15)	−0.0048 (12)	−0.0163 (12)	0.0037 (11)
C47	0.0386 (18)	0.0296 (15)	0.048 (2)	−0.0061 (13)	−0.0272 (16)	0.0071 (14)
O48	0.0280 (11)	0.0171 (9)	0.0315 (11)	−0.0056 (8)	−0.0123 (8)	0.0037 (7)
C49	0.0195 (13)	0.0189 (12)	0.0194 (12)	−0.0032 (10)	−0.0036 (10)	−0.0010 (9)
N50	0.0208 (11)	0.0138 (9)	0.0268 (11)	−0.0020 (8)	−0.0092 (9)	0.0011 (8)
C51	0.0227 (13)	0.0167 (12)	0.0300 (14)	−0.0013 (10)	−0.0122 (11)	0.0027 (10)
C52	0.0163 (12)	0.0184 (12)	0.0244 (13)	−0.0007 (10)	−0.0069 (10)	0.0043 (10)
N53	0.0161 (11)	0.0213 (11)	0.0236 (11)	−0.0032 (9)	−0.0058 (9)	0.0062 (9)
N54	0.0191 (11)	0.0169 (10)	0.0225 (11)	−0.0036 (8)	−0.0051 (9)	0.0058 (8)
C55	0.0196 (13)	0.0174 (12)	0.0177 (12)	−0.0033 (10)	−0.0050 (10)	0.0018 (9)
C56	0.0164 (12)	0.0177 (12)	0.0179 (12)	−0.0013 (9)	−0.0024 (10)	0.0003 (10)
C57	0.0205 (13)	0.0217 (13)	0.0197 (12)	−0.0044 (10)	−0.0058 (10)	0.0018 (10)
C58	0.0228 (13)	0.0228 (12)	0.0266 (14)	−0.0082 (10)	−0.0050 (11)	0.0016 (10)
C59	0.0218 (13)	0.0219 (12)	0.0242 (13)	−0.0068 (10)	−0.0028 (10)	0.0045 (10)
O60	0.0367 (12)	0.0408 (12)	0.0418 (12)	−0.0235 (10)	−0.0211 (10)	0.0241 (10)
C61	0.0307 (15)	0.0259 (14)	0.0305 (14)	−0.0155 (12)	−0.0127 (12)	0.0127 (11)
C62	0.0324 (16)	0.0436 (18)	0.0317 (15)	−0.0162 (14)	−0.0063 (13)	−0.0001 (13)
C63	0.0311 (17)	0.0350 (17)	0.0482 (19)	−0.0062 (13)	−0.0099 (14)	0.0024 (14)
C64	0.0301 (16)	0.0308 (15)	0.0394 (17)	−0.0120 (13)	−0.0146 (13)	0.0132 (13)
C65	0.0388 (17)	0.0362 (16)	0.0302 (15)	−0.0209 (14)	−0.0107 (13)	0.0046 (12)
C66	0.0341 (17)	0.0215 (13)	0.0386 (17)	−0.0126 (12)	−0.0101 (13)	0.0076 (12)
C67	0.0212 (13)	0.0254 (13)	0.0199 (12)	−0.0051 (10)	−0.0092 (10)	0.0054 (10)
C68	0.0174 (12)	0.0192 (12)	0.0212 (13)	−0.0032 (10)	−0.0019 (10)	−0.0009 (10)
C69	0.0145 (12)	0.0178 (11)	0.0205 (12)	−0.0025 (10)	−0.0047 (10)	−0.0017 (9)
C70	0.0193 (13)	0.0157 (11)	0.0189 (12)	−0.0042 (10)	−0.0062 (10)	0.0015 (9)
N71	0.0192 (11)	0.0169 (10)	0.0229 (11)	−0.0031 (9)	−0.0055 (9)	0.0034 (8)
C72	0.0214 (13)	0.0177 (11)	0.0201 (12)	−0.0072 (10)	−0.0019 (10)	0.0008 (9)
N73	0.0156 (11)	0.0166 (10)	0.0250 (11)	−0.0033 (8)	−0.0024 (9)	−0.0021 (8)
C74	0.0199 (13)	0.0172 (11)	0.0181 (12)	−0.0029 (10)	−0.0041 (10)	−0.0029 (9)
N75	0.0137 (10)	0.0189 (10)	0.0260 (11)	−0.0016 (8)	−0.0054 (9)	0.0038 (9)
C76	0.0239 (13)	0.0189 (12)	0.0285 (13)	−0.0024 (10)	−0.0121 (11)	0.0024 (10)
C77	0.0222 (13)	0.0152 (11)	0.0262 (13)	−0.0003 (9)	−0.0101 (11)	0.0012 (9)
C78	0.0232 (13)	0.0161 (11)	0.0259 (13)	−0.0043 (10)	−0.0086 (10)	0.0027 (9)
C79	0.0232 (14)	0.0180 (12)	0.0293 (14)	−0.0033 (10)	−0.0071 (11)	0.0034 (10)
C80	0.0319 (17)	0.0253 (14)	0.0366 (17)	−0.0015 (12)	−0.0164 (13)	−0.0006 (12)

Geometric parameters (Å, º)

Br1—C2	1.907 (3)	C41—C42	1.381 (5)
C2—C3	1.371 (5)	C41—H411	0.931
C2—C7	1.389 (4)	C42—C43	1.384 (4)
C3—C4	1.389 (5)	C42—H421	0.956
C3—H31	0.943	C43—H431	0.959
C4—C5	1.378 (5)	C44—C45	1.386 (4)
C4—H41	0.963	C44—H441	0.947
C5—C6	1.377 (5)	C45—H451	0.928
C5—H51	0.934	C46—C47	1.308 (5)
C6—C7	1.382 (5)	C46—H461	0.952
C6—H61	0.931	C47—H471	0.937
C7—H71	0.943	C47—H472	0.947
Br8—C9	1.903 (3)	O48—C49	1.234 (3)
C9—C10	1.382 (5)	C49—N50	1.350 (4)
C9—C14	1.379 (5)	C49—C79	1.499 (4)
C10—C11	1.389 (5)	N50—C51	1.462 (3)
C10—H101	0.939	N50—C78	1.467 (3)
C11—C12	1.399 (5)	C51—C52	1.533 (4)
C11—H111	0.947	C51—H511	0.979
C12—C13	1.327 (6)	C51—H512	0.979
C12—H121	0.925	C52—N53	1.458 (3)
C13—C14	1.398 (5)	C52—C76	1.526 (4)
C13—H131	0.927	C52—H521	0.989
C14—H141	0.946	N53—N54	1.373 (3)
O15—C16	1.221 (3)	N53—C70	1.358 (3)
C16—N17	1.367 (4)	N54—C55	1.320 (4)
C16—C46	1.498 (4)	C55—C56	1.482 (3)
N17—C18	1.466 (3)	C55—C69	1.433 (4)
N17—C22	1.465 (3)	C56—C57	1.406 (4)
C18—C19	1.507 (4)	C56—C68	1.386 (4)
C18—H181	0.974	C57—C58	1.383 (4)
C18—H182	0.997	C57—H571	0.953
C19—C20	1.543 (4)	C58—C59	1.376 (4)
C19—H192	0.978	C58—H581	0.960
C19—H191	0.976	C59—O60	1.379 (3)
C20—C21	1.527 (4)	C59—C67	1.391 (4)
C20—H201	0.983	O60—C61	1.400 (4)
C20—H202	0.976	C61—C62	1.378 (5)
C21—C22	1.531 (4)	C61—C66	1.377 (5)
C21—N23	1.459 (3)	C62—C63	1.384 (5)
C21—H211	0.992	C62—H621	0.943
C22—H221	0.974	C63—C64	1.384 (5)
C22—H222	0.969	C63—H631	0.934
N23—N24	1.371 (3)	C64—C65	1.390 (5)
N23—C27	1.358 (3)	C64—H641	0.952
N24—C25	1.317 (3)	C65—C66	1.383 (5)
C25—C26	1.431 (3)	C65—H651	0.939
C25—C33	1.478 (3)	C66—H661	0.943
C26—C27	1.397 (4)	C67—C68	1.397 (4)
C26—C31	1.417 (4)	C67—H671	0.932
C27—N28	1.355 (3)	C68—H681	0.942
N28—C29	1.322 (4)	C69—C70	1.401 (4)
C29—N30	1.340 (3)	C69—C74	1.424 (4)
C29—H291	0.962	C70—N71	1.361 (3)
N30—C31	1.363 (3)	N71—C72	1.332 (4)
C31—N32	1.329 (3)	C72—N73	1.341 (3)
N32—H322	0.843 (18)	C72—H721	0.948
N32—H321	0.833 (18)	N73—C74	1.351 (3)
C33—C34	1.393 (4)	C74—N75	1.319 (3)
C33—C45	1.400 (4)	N75—H752	0.850 (18)
C34—C35	1.391 (4)	N75—H751	0.844 (18)
C34—H341	0.964	C76—C77	1.536 (4)
C35—C36	1.387 (4)	C76—H761	0.973
C35—H351	0.942	C76—H762	0.984
C36—O37	1.388 (3)	C77—C78	1.527 (4)
C36—C44	1.375 (4)	C77—H772	0.970
O37—C38	1.386 (3)	C77—H771	0.974
C38—C39	1.388 (4)	C78—H781	0.977
C38—C43	1.375 (4)	C78—H782	0.979
C39—C40	1.388 (4)	C79—C80	1.300 (5)
C39—H391	0.937	C79—H791	0.950
C40—C41	1.386 (4)	C80—H801	0.945
C40—H401	0.934	C80—H802	0.953
Br1—C2—C3	118.4 (2)	C41—C42—C43	120.6 (3)
Br1—C2—C7	119.3 (2)	C41—C42—H421	119.8
C3—C2—C7	122.2 (3)	C43—C42—H421	119.6
C2—C3—C4	118.6 (3)	C42—C43—C38	119.2 (3)
C2—C3—H31	121.3	C42—C43—H431	121.4
C4—C3—H31	120.1	C38—C43—H431	119.4
C3—C4—C5	120.4 (3)	C36—C44—C45	120.1 (3)
C3—C4—H41	119.6	C36—C44—H441	119.3
C5—C4—H41	120.0	C45—C44—H441	120.7
C4—C5—C6	119.7 (3)	C33—C45—C44	120.3 (3)
C4—C5—H51	120.6	C33—C45—H451	120.0
C6—C5—H51	119.7	C44—C45—H451	119.8
C5—C6—C7	121.3 (3)	C16—C46—C47	120.7 (3)
C5—C6—H61	120.1	C16—C46—H461	119.7
C7—C6—H61	118.6	C47—C46—H461	119.5
C2—C7—C6	117.7 (3)	C46—C47—H471	119.8
C2—C7—H71	120.5	C46—C47—H472	119.4
C6—C7—H71	121.8	H471—C47—H472	120.7
Br8—C9—C10	118.0 (2)	O48—C49—N50	122.7 (2)
Br8—C9—C14	120.4 (3)	O48—C49—C79	120.0 (3)
C10—C9—C14	121.6 (3)	N50—C49—C79	117.3 (2)
C9—C10—C11	118.7 (3)	C49—N50—C51	119.9 (2)
C9—C10—H101	120.4	C49—N50—C78	127.3 (2)
C11—C10—H101	120.9	C51—N50—C78	112.6 (2)
C10—C11—C12	119.3 (3)	N50—C51—C52	110.0 (2)
C10—C11—H111	119.3	N50—C51—H511	109.3
C12—C11—H111	121.3	C52—C51—H511	108.9
C11—C12—C13	121.0 (3)	N50—C51—H512	107.4
C11—C12—H121	119.0	C52—C51—H512	110.4
C13—C12—H121	120.0	H511—C51—H512	110.9
C12—C13—C14	121.3 (3)	C51—C52—N53	108.9 (2)
C12—C13—H131	118.7	C51—C52—C76	112.2 (2)
C14—C13—H131	120.0	N53—C52—C76	112.4 (2)
C13—C14—C9	118.1 (3)	C51—C52—H521	109.3
C13—C14—H141	122.0	N53—C52—H521	105.5
C9—C14—H141	119.9	C76—C52—H521	108.2
O15—C16—N17	122.1 (3)	C52—N53—N54	117.8 (2)
O15—C16—C46	121.9 (3)	C52—N53—C70	131.3 (2)
N17—C16—C46	115.9 (2)	N54—N53—C70	110.7 (2)
C16—N17—C18	121.7 (2)	N53—N54—C55	107.0 (2)
C16—N17—C22	118.0 (2)	N54—C55—C56	118.5 (2)
C18—N17—C22	113.8 (2)	N54—C55—C69	110.5 (2)
N17—C18—C19	111.1 (2)	C56—C55—C69	131.0 (2)
N17—C18—H181	108.2	C55—C56—C57	117.7 (2)
C19—C18—H181	109.1	C55—C56—C68	123.1 (2)
N17—C18—H182	108.9	C57—C56—C68	119.1 (2)
C19—C18—H182	109.1	C56—C57—C58	120.2 (3)
H181—C18—H182	110.4	C56—C57—H571	119.7
C18—C19—C20	110.5 (2)	C58—C57—H571	120.1
C18—C19—H192	108.7	C57—C58—C59	120.0 (3)
C20—C19—H192	107.1	C57—C58—H581	120.2
C18—C19—H191	109.4	C59—C58—H581	119.7
C20—C19—H191	109.7	C58—C59—O60	114.6 (2)
H192—C19—H191	111.4	C58—C59—C67	121.0 (2)
C19—C20—C21	109.9 (2)	O60—C59—C67	124.5 (3)
C19—C20—H201	108.6	C59—O60—C61	118.9 (2)
C21—C20—H201	109.4	O60—C61—C62	118.8 (3)
C19—C20—H202	110.9	O60—C61—C66	118.6 (3)
C21—C20—H202	109.4	C62—C61—C66	122.2 (3)
H201—C20—H202	108.6	C61—C62—C63	118.4 (3)
C20—C21—C22	111.7 (2)	C61—C62—H621	119.6
C20—C21—N23	110.2 (2)	C63—C62—H621	122.0
C22—C21—N23	109.1 (2)	C62—C63—C64	120.5 (3)
C20—C21—H211	108.9	C62—C63—H631	119.8
C22—C21—H211	109.4	C64—C63—H631	119.8
N23—C21—H211	107.4	C63—C64—C65	120.1 (3)
C21—C22—N17	109.4 (2)	C63—C64—H641	120.1
C21—C22—H221	110.7	C65—C64—H641	119.8
N17—C22—H221	108.5	C64—C65—C66	119.7 (3)
C21—C22—H222	110.7	C64—C65—H651	120.3
N17—C22—H222	109.7	C66—C65—H651	120.0
H221—C22—H222	107.8	C65—C66—C61	119.0 (3)
C21—N23—N24	119.9 (2)	C65—C66—H661	121.8
C21—N23—C27	129.4 (2)	C61—C66—H661	119.1
N24—N23—C27	110.4 (2)	C59—C67—C68	119.0 (3)
N23—N24—C25	107.2 (2)	C59—C67—H671	119.7
N24—C25—C26	110.4 (2)	C68—C67—H671	121.3
N24—C25—C33	118.2 (2)	C67—C68—C56	120.7 (3)
C26—C25—C33	131.2 (2)	C67—C68—H681	118.7
C25—C26—C27	104.3 (2)	C56—C68—H681	120.6
C25—C26—C31	139.5 (2)	C55—C69—C70	104.3 (2)
C27—C26—C31	116.1 (2)	C55—C69—C74	138.9 (2)
C26—C27—N23	107.6 (2)	C70—C69—C74	116.6 (2)
C26—C27—N28	126.8 (2)	C69—C70—N53	107.4 (2)
N23—C27—N28	125.6 (2)	C69—C70—N71	126.4 (2)
C27—N28—C29	111.0 (2)	N53—C70—N71	126.2 (2)
N28—C29—N30	129.4 (2)	C70—N71—C72	110.7 (2)
N28—C29—H291	114.7	N71—C72—N73	129.5 (2)
N30—C29—H291	116.0	N71—C72—H721	115.1
C29—N30—C31	118.7 (2)	N73—C72—H721	115.4
C26—C31—N30	117.7 (2)	C72—N73—C74	119.2 (2)
C26—C31—N32	125.7 (2)	C69—C74—N73	117.5 (2)
N30—C31—N32	116.6 (2)	C69—C74—N75	124.8 (2)
C31—N32—H322	122.5 (15)	N73—C74—N75	117.7 (2)
C31—N32—H321	118.1 (15)	C74—N75—H752	121.8 (15)
H322—N32—H321	119 (2)	C74—N75—H751	120.1 (15)
C25—C33—C34	121.3 (2)	H752—N75—H751	117 (2)
C25—C33—C45	119.8 (2)	C52—C76—C77	109.5 (2)
C34—C33—C45	118.6 (2)	C52—C76—H761	110.1
C33—C34—C35	121.2 (3)	C77—C76—H761	108.3
C33—C34—H341	119.2	C52—C76—H762	109.4
C35—C34—H341	119.6	C77—C76—H762	109.3
C34—C35—C36	118.8 (3)	H761—C76—H762	110.2
C34—C35—H351	121.7	C76—C77—C78	110.7 (2)
C36—C35—H351	119.5	C76—C77—H772	109.2
C35—C36—O37	121.6 (3)	C78—C77—H772	109.0
C35—C36—C44	121.0 (2)	C76—C77—H771	109.2
O37—C36—C44	117.3 (3)	C78—C77—H771	109.2
C36—O37—C38	119.6 (2)	H772—C77—H771	109.5
O37—C38—C39	121.7 (3)	C77—C78—N50	109.7 (2)
O37—C38—C43	116.9 (3)	C77—C78—H781	109.3
C39—C38—C43	121.3 (3)	N50—C78—H781	111.1
C38—C39—C40	118.9 (3)	C77—C78—H782	109.7
C38—C39—H391	120.3	N50—C78—H782	107.3
C40—C39—H391	120.9	H781—C78—H782	109.7
C39—C40—C41	120.3 (3)	C49—C79—C80	121.9 (3)
C39—C40—H401	119.3	C49—C79—H791	118.4
C41—C40—H401	120.4	C80—C79—H791	119.7
C40—C41—C42	119.6 (3)	C79—C80—H801	118.8
C40—C41—H411	121.3	C79—C80—H802	120.4
C42—C41—H411	119.0	H801—C80—H802	120.9

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C3—H31···N24	0.94	2.47	3.373 (4)	160 (1)
C5—H51···O15^i	0.93	2.41	3.316 (4)	164 (1)
C10—H101···N54	0.94	2.48	3.285 (4)	144 (1)
C76—H762···N71	0.98	2.53	3.185 (4)	124 (1)
N75—H752···O15	0.85	2.40	3.047 (4)	133 (2)
N75—H752···C68	0.85	2.59	3.298 (4)	142 (2)
N32—H322···O48	0.84	2.26	2.957 (4)	141 (2)
N75—H751···N30^ii	0.84	2.11	2.931 (4)	166 (3)
N32—H321···N73^iii	0.83	2.15	2.976 (4)	172 (3)

Symmetry codes: (i) x, y, z+1; (ii) x−1, y, z; (iii) x+1, y, z.

(iodo)

Crystal data

C31H29.00IN6O2	Z = 2
Mr = 644.51	F(000) = 651.996
Triclinic, P1	Dx = 1.526 Mg m^−3
a = 11.0044 (2) Å	Cu Kα radiation, λ = 1.54180 Å
b = 11.9170 (2) Å	Cell parameters from 20836 reflections
c = 12.1547 (1) Å	θ = 4–75°
α = 79.7701 (11)°	µ = 9.29 mm^−1
β = 71.2027 (13)°	T = 95 K
γ = 68.7521 (15)°	Prism, colorless
V = 1403.02 (1) Å^3	0.26 × 0.11 × 0.08 mm

Data collection

Oxford Diffraction SuperNova diffractometer	10563 reflections with I > 2.0σ(I)
Graphite monochromator	Rint = 0.017
ω scans	θmax = 74.8°, θmin = 3.9°
Absorption correction: multi-scan CrysAlisPro, (Agilent, 2011)	h = −12→13
Tmin = 0.20, Tmax = 0.50	k = −14→14
24897 measured reflections	l = −15→15
10634 independent reflections

Refinement

Refinement on F^2	Hydrogen site location: difference Fourier map
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.028	Method = Modified Sheldrick w = 1/[σ^2(F^2) + ( 0.03P)^2 + 2.72P] , where P = (max(Fo^2,0) + 2Fc^2)/3
wR(F^2) = 0.070	(Δ/σ)max = 0.001
S = 1.00	Δρmax = 1.56 e Å^−3
10634 reflections	Δρmin = −1.01 e Å^−3
734 parameters	Absolute structure: Flack (1983), 4967 Friedel-pairs
109 restraints	Absolute structure parameter: 0.000 (3)
Primary atom site location: structure-invariant direct methods

Special details

Experimental. The crystal was placed in the cold stream of an Oxford Cryosystems open-flow nitrogen cryostat (Cosier & Glazer, 1986) with a nominal stability of 0.1K.

Cosier, J. & Glazer, A.M., 1986. J. Appl. Cryst. 105-107.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
C1	0.5000 (5)	0.5000 (4)	1.5000 (4)	0.0266
C2	0.4371 (4)	0.4820 (4)	1.4321 (4)	0.0204
C3	0.3397 (4)	0.5849 (3)	1.3811 (3)	0.0166
O4	0.3497 (3)	0.6867 (2)	1.3653 (3)	0.0201
N5	0.2422 (3)	0.5608 (2)	1.3542 (2)	0.0166
C6	0.2149 (3)	0.4453 (3)	1.3760 (3)	0.0164
C7	0.2255 (3)	0.4034 (3)	1.2609 (3)	0.0172
C8	0.1241 (4)	0.4982 (3)	1.2020 (3)	0.0185
C9	0.1452 (4)	0.6197 (3)	1.1892 (3)	0.0168
C10	0.1427 (4)	0.6566 (3)	1.3046 (3)	0.0188
N11	0.0440 (3)	0.7155 (3)	1.1417 (3)	0.0162
C12	−0.0929 (4)	0.7474 (3)	1.1702 (3)	0.0140
N13	−0.1728 (3)	0.6930 (3)	1.2545 (3)	0.0166
C14	−0.3023 (4)	0.7477 (3)	1.2601 (3)	0.0166
N15	−0.3613 (3)	0.8460 (3)	1.1975 (3)	0.0140
C16	−0.2804 (4)	0.9012 (3)	1.1165 (3)	0.0143
N17	−0.3421 (3)	1.0013 (3)	1.0602 (3)	0.0156
C18	−0.1386 (4)	0.8499 (3)	1.0970 (3)	0.0136
C19	−0.0173 (4)	0.8741 (3)	1.0274 (3)	0.0148
N20	0.0907 (3)	0.7943 (3)	1.0553 (3)	0.0168
C21	0.0028 (4)	0.9716 (3)	0.9362 (3)	0.0139
C22	0.0970 (4)	1.0261 (3)	0.9344 (3)	0.0155
C23	0.1189 (4)	1.1173 (3)	0.8513 (3)	0.0183
C24	0.0481 (4)	1.1539 (3)	0.7682 (3)	0.0181
C25	−0.0430 (4)	1.0997 (3)	0.7664 (3)	0.0192
C26	−0.0653 (4)	1.0082 (3)	0.8517 (3)	0.0160
O27	0.0785 (3)	1.2448 (3)	0.6884 (3)	0.0293
C28	−0.0085 (4)	1.3056 (3)	0.6187 (3)	0.0221
C29	−0.1110 (4)	1.4112 (4)	0.6554 (4)	0.0303
C30	−0.1873 (5)	1.4792 (4)	0.5799 (4)	0.0331
C31	−0.1618 (5)	1.4388 (4)	0.4716 (4)	0.0268
C32	−0.0611 (4)	1.3314 (4)	0.4385 (3)	0.0263
C33	0.0181 (4)	1.2635 (3)	0.5127 (4)	0.0229
C34	−0.5437 (5)	1.4395 (4)	0.8358 (5)	0.0338
C35	−0.4697 (5)	1.4510 (4)	0.8932 (4)	0.0210
C36	−0.3821 (4)	1.3439 (3)	0.9499 (3)	0.0164
O37	−0.3551 (3)	1.2413 (2)	0.9243 (3)	0.0227
N38	−0.3291 (3)	1.3681 (2)	1.0272 (2)	0.0165
C39	−0.4032 (3)	1.4690 (3)	1.1032 (3)	0.0201
C40	−0.3073 (4)	1.5173 (3)	1.1280 (3)	0.0246
C41	−0.2025 (4)	1.4171 (3)	1.1793 (3)	0.0199
C42	−0.1301 (4)	1.3117 (3)	1.0996 (3)	0.0142
C43	−0.2310 (3)	1.2674 (3)	1.0741 (3)	0.0162
N44	−0.0384 (3)	1.2110 (3)	1.1533 (3)	0.0135
C45	0.0962 (4)	1.1838 (3)	1.1377 (3)	0.0137
N46	0.1770 (3)	1.2425 (3)	1.0608 (3)	0.0139
C47	0.3044 (4)	1.1929 (3)	1.0660 (3)	0.0150
N48	0.3591 (3)	1.0952 (3)	1.1307 (3)	0.0145
C49	0.2763 (4)	1.0343 (3)	1.2034 (3)	0.0121
N50	0.3366 (3)	0.9319 (3)	1.2580 (3)	0.0150
C51	0.1354 (4)	1.0840 (3)	1.2142 (3)	0.0126
C52	0.0130 (4)	1.0592 (3)	1.2766 (3)	0.0136
N53	−0.0905 (3)	1.1370 (3)	1.2397 (3)	0.0152
C54	−0.0165 (4)	0.9722 (3)	1.3747 (3)	0.0152
C55	0.0493 (4)	0.9431 (3)	1.4629 (3)	0.0151
C56	0.0132 (4)	0.8689 (3)	1.5601 (3)	0.0197
C57	−0.0894 (4)	0.8233 (3)	1.5705 (3)	0.0202
C58	−0.1547 (4)	0.8493 (3)	1.4837 (3)	0.0188
C59	−0.1185 (4)	0.9239 (3)	1.3866 (3)	0.0168
O60	−0.1379 (3)	0.7564 (3)	1.6689 (2)	0.0318
C61	−0.0463 (4)	0.6744 (3)	1.7264 (3)	0.0185
C62	0.0701 (4)	0.5900 (4)	1.6662 (3)	0.0232
C63	0.1501 (5)	0.5017 (4)	1.7276 (4)	0.0270
C64	0.1114 (5)	0.4990 (4)	1.8484 (4)	0.0303
C65	−0.0022 (4)	0.5854 (4)	1.9070 (3)	0.0308
C66	−0.0830 (4)	0.6743 (4)	1.8454 (3)	0.0223
C67	−0.4737 (5)	1.1461 (4)	1.5069 (4)	0.0233
C68	−0.3551 (5)	1.1680 (4)	1.4910 (4)	0.0240
C69	−0.3159 (5)	1.1729 (4)	1.5879 (4)	0.0247
C70	−0.3995 (4)	1.1610 (4)	1.7005 (4)	0.0247
C71	−0.5214 (4)	1.1405 (4)	1.7137 (4)	0.0280
C72	−0.5599 (4)	1.1360 (4)	1.6164 (4)	0.0268
I73	−0.52205 (5)	1.12546 (4)	1.35928 (4)	0.0256
C74	0.4447 (5)	0.8038 (5)	0.7980 (4)	0.0293
C75	0.3330 (5)	0.7684 (4)	0.8125 (4)	0.0281
C76	0.2982 (5)	0.7644 (4)	0.7124 (4)	0.0284
C77	0.3742 (5)	0.8036 (4)	0.6035 (4)	0.0303
C78	0.4754 (5)	0.8356 (4)	0.5922 (4)	0.0325
C79	0.5183 (5)	0.8384 (4)	0.6891 (4)	0.0314
I80	0.49236 (5)	0.81685 (4)	0.94919 (5)	0.0350
H11	0.4856	0.5791	1.5164	0.0328*
H12	0.5592	0.4332	1.5320	0.0320*
H21	0.4516	0.4034	1.4165	0.0252*
H61	0.2774	0.3839	1.4144	0.0214*
H62	0.1234	0.4597	1.4273	0.0214*
H72	0.3169	0.3946	1.2106	0.0186*
H71	0.2104	0.3270	1.2732	0.0182*
H81	0.1394	0.4742	1.1245	0.0235*
H82	0.0325	0.5056	1.2488	0.0239*
H91	0.2349	0.6130	1.1340	0.0222*
H101	0.1661	0.7297	1.2898	0.0232*
H102	0.0516	0.6712	1.3587	0.0233*
H141	−0.3613	0.7123	1.3157	0.0195*
H221	0.1466	1.0013	0.9895	0.0214*
H231	0.1819	1.1531	0.8505	0.0242*
H251	−0.0860	1.1236	0.7088	0.0210*
H261	−0.1249	0.9705	0.8520	0.0194*
H291	−0.1288	1.4351	0.7296	0.0374*
H301	−0.2551	1.5519	0.6029	0.0392*
H311	−0.2138	1.4830	0.4208	0.0307*
H321	−0.0447	1.3029	0.3665	0.0302*
H331	0.0871	1.1910	0.4911	0.0276*
H341	−0.5979	1.5072	0.8011	0.0409*
H342	−0.5457	1.3631	0.8278	0.0406*
H351	−0.4725	1.5271	0.9015	0.0245*
H392	−0.4644	1.5334	1.0673	0.0248*
H391	−0.4544	1.4382	1.1771	0.0247*
H402	−0.3571	1.5806	1.1826	0.0298*
H401	−0.2568	1.5479	1.0536	0.0299*
H411	−0.1347	1.4471	1.1871	0.0260*
H412	−0.2508	1.3895	1.2542	0.0260*
H421	−0.0766	1.3388	1.0260	0.0181*
H431	−0.2786	1.2308	1.1436	0.0212*
H432	−0.1836	1.2080	1.0163	0.0210*
H471	0.3651	1.2314	1.0165	0.0188*
H551	0.1217	0.9747	1.4541	0.0197*
H561	0.0602	0.8495	1.6177	0.0263*
H581	−0.2201	0.8149	1.4909	0.0250*
H591	−0.1617	0.9429	1.3274	0.0199*
H621	0.0928	0.5925	1.5851	0.0282*
H631	0.2293	0.4458	1.6877	0.0304*
H641	0.1602	0.4368	1.8887	0.0366*
H651	−0.0237	0.5845	1.9884	0.0383*
H661	−0.1632	0.7334	1.8833	0.0267*
H681	−0.3007	1.1788	1.4156	0.0303*
H691	−0.2320	1.1850	1.5773	0.0350*
H701	−0.3766	1.1682	1.7642	0.0261*
H711	−0.5738	1.1267	1.7892	0.0472*
H721	−0.6414	1.1239	1.6262	0.0401*
H751	0.2815	0.7480	0.8869	0.0286*
H761	0.2277	0.7369	0.7179	0.0328*
H791	0.5947	0.8614	0.6809	0.0420*
H172	−0.297 (3)	1.044 (3)	1.016 (3)	0.0193*
H771	0.3497	0.8048	0.5392	0.0364*
H501	0.423 (2)	0.909 (3)	1.244 (3)	0.0202*
H502	0.290 (3)	0.889 (3)	1.299 (4)	0.0206*
H781	0.5232	0.8582	0.5198	0.0512*
H171	−0.427 (2)	1.038 (3)	1.086 (3)	0.0187*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.026 (2)	0.0234 (19)	0.033 (2)	−0.0002 (16)	−0.0198 (18)	−0.0044 (16)
C2	0.019 (2)	0.0184 (18)	0.0235 (19)	−0.0027 (15)	−0.0102 (16)	0.0006 (15)
C3	0.0194 (18)	0.0162 (16)	0.0137 (16)	−0.0049 (14)	−0.0061 (14)	0.0004 (12)
O4	0.0222 (14)	0.0151 (12)	0.0257 (14)	−0.0072 (10)	−0.0117 (11)	0.0033 (10)
N5	0.0192 (14)	0.0107 (12)	0.0222 (14)	−0.0024 (11)	−0.0138 (12)	0.0021 (10)
C6	0.0212 (17)	0.0099 (13)	0.0194 (15)	−0.0046 (12)	−0.0102 (13)	0.0037 (11)
C7	0.0170 (16)	0.0119 (14)	0.0233 (16)	−0.0009 (12)	−0.0112 (14)	−0.0003 (12)
C8	0.0201 (17)	0.0162 (15)	0.0215 (16)	−0.0035 (13)	−0.0132 (14)	0.0018 (12)
C9	0.0097 (16)	0.0163 (15)	0.0197 (17)	−0.0002 (13)	−0.0063 (13)	0.0060 (13)
C10	0.0187 (17)	0.0110 (14)	0.0279 (18)	−0.0007 (12)	−0.0148 (14)	0.0023 (12)
N11	0.0108 (15)	0.0167 (14)	0.0188 (14)	−0.0027 (11)	−0.0063 (11)	0.0048 (11)
C12	0.0153 (18)	0.0122 (15)	0.0132 (16)	−0.0022 (13)	−0.0071 (13)	0.0030 (12)
N13	0.0151 (15)	0.0156 (13)	0.0180 (14)	−0.0046 (12)	−0.0053 (12)	0.0017 (11)
C14	0.0178 (18)	0.0152 (15)	0.0159 (16)	−0.0078 (14)	−0.0026 (13)	0.0021 (12)
N15	0.0099 (14)	0.0140 (13)	0.0190 (14)	−0.0049 (11)	−0.0035 (11)	−0.0019 (11)
C16	0.0166 (18)	0.0118 (14)	0.0147 (16)	−0.0031 (13)	−0.0068 (13)	−0.0003 (12)
N17	0.0076 (14)	0.0144 (14)	0.0217 (15)	−0.0015 (11)	−0.0043 (12)	0.0025 (12)
C18	0.0120 (17)	0.0151 (15)	0.0133 (16)	−0.0019 (13)	−0.0067 (13)	0.0005 (12)
C19	0.0118 (17)	0.0162 (16)	0.0148 (16)	−0.0024 (13)	−0.0053 (13)	0.0012 (13)
N20	0.0143 (15)	0.0172 (15)	0.0173 (15)	−0.0045 (12)	−0.0074 (12)	0.0074 (11)
C21	0.0106 (17)	0.0152 (16)	0.0113 (16)	−0.0011 (13)	−0.0018 (13)	0.0012 (13)
C22	0.0110 (17)	0.0209 (17)	0.0144 (16)	−0.0039 (14)	−0.0051 (13)	−0.0008 (13)
C23	0.0162 (18)	0.0192 (17)	0.0215 (18)	−0.0067 (14)	−0.0085 (14)	0.0018 (14)
C24	0.0166 (17)	0.0206 (17)	0.0175 (17)	−0.0100 (14)	−0.0039 (14)	0.0049 (13)
C25	0.0212 (19)	0.0235 (18)	0.0147 (16)	−0.0067 (15)	−0.0117 (14)	0.0055 (13)
C26	0.0124 (17)	0.0188 (17)	0.0186 (18)	−0.0071 (14)	−0.0048 (14)	−0.0009 (13)
O27	0.0287 (15)	0.0381 (15)	0.0328 (14)	−0.0244 (12)	−0.0218 (12)	0.0225 (12)
C28	0.027 (2)	0.028 (2)	0.0217 (18)	−0.0203 (17)	−0.0161 (16)	0.0153 (15)
C29	0.028 (2)	0.041 (2)	0.0245 (19)	−0.0168 (19)	−0.0068 (16)	−0.0003 (17)
C30	0.023 (2)	0.033 (2)	0.039 (2)	−0.0065 (18)	−0.0101 (18)	0.0030 (19)
C31	0.024 (2)	0.030 (2)	0.031 (2)	−0.0130 (17)	−0.0157 (17)	0.0123 (17)
C32	0.037 (2)	0.032 (2)	0.0208 (19)	−0.0235 (18)	−0.0137 (17)	0.0080 (15)
C33	0.025 (2)	0.0183 (16)	0.029 (2)	−0.0129 (15)	−0.0111 (17)	0.0080 (15)
C34	0.044 (3)	0.024 (2)	0.040 (3)	−0.0050 (19)	−0.027 (2)	−0.0006 (18)
C35	0.027 (2)	0.0138 (17)	0.025 (2)	−0.0034 (15)	−0.0156 (17)	0.0011 (14)
C36	0.0127 (17)	0.0176 (17)	0.0188 (17)	−0.0019 (13)	−0.0087 (13)	0.0008 (13)
O37	0.0291 (15)	0.0167 (12)	0.0270 (14)	−0.0045 (11)	−0.0186 (12)	0.0001 (10)
N38	0.0149 (14)	0.0164 (13)	0.0197 (14)	−0.0001 (11)	−0.0113 (11)	−0.0033 (11)
C39	0.0147 (16)	0.0189 (16)	0.0263 (17)	0.0001 (13)	−0.0088 (14)	−0.0069 (13)
C40	0.0261 (19)	0.0187 (16)	0.033 (2)	−0.0007 (14)	−0.0179 (16)	−0.0066 (14)
C41	0.0214 (18)	0.0188 (15)	0.0225 (17)	−0.0040 (14)	−0.0125 (14)	−0.0022 (13)
C42	0.0117 (17)	0.0155 (15)	0.0150 (15)	−0.0033 (13)	−0.0068 (13)	0.0032 (12)
C43	0.0153 (16)	0.0144 (15)	0.0192 (15)	−0.0017 (12)	−0.0100 (13)	0.0012 (12)
N44	0.0118 (15)	0.0142 (13)	0.0127 (13)	−0.0024 (11)	−0.0068 (11)	0.0056 (10)
C45	0.0116 (17)	0.0167 (15)	0.0144 (16)	−0.0032 (13)	−0.0064 (13)	−0.0033 (12)
N46	0.0137 (15)	0.0143 (13)	0.0130 (13)	−0.0043 (12)	−0.0046 (11)	0.0019 (10)
C47	0.0107 (16)	0.0154 (15)	0.0176 (16)	−0.0029 (13)	−0.0032 (13)	−0.0026 (12)
N48	0.0128 (14)	0.0144 (13)	0.0169 (14)	−0.0044 (11)	−0.0057 (11)	0.0004 (10)
C49	0.0108 (17)	0.0158 (15)	0.0112 (15)	−0.0043 (13)	−0.0038 (12)	−0.0034 (12)
N50	0.0125 (15)	0.0123 (13)	0.0191 (15)	−0.0022 (11)	−0.0073 (12)	0.0028 (11)
C51	0.0142 (18)	0.0121 (15)	0.0119 (15)	−0.0047 (13)	−0.0045 (13)	0.0004 (12)
C52	0.0138 (17)	0.0143 (15)	0.0139 (16)	−0.0029 (13)	−0.0083 (13)	0.0006 (13)
N53	0.0136 (15)	0.0174 (14)	0.0143 (14)	−0.0067 (12)	−0.0040 (11)	0.0030 (11)
C54	0.0126 (18)	0.0141 (16)	0.0175 (18)	−0.0029 (14)	−0.0043 (14)	−0.0003 (13)
C55	0.0132 (17)	0.0169 (16)	0.0149 (16)	−0.0036 (14)	−0.0060 (13)	0.0011 (13)
C56	0.0135 (17)	0.0254 (18)	0.0187 (17)	−0.0037 (14)	−0.0075 (14)	0.0025 (14)
C57	0.0146 (17)	0.0203 (17)	0.0169 (17)	−0.0025 (13)	−0.0018 (13)	0.0087 (13)
C58	0.0095 (16)	0.0215 (17)	0.0236 (18)	−0.0058 (13)	−0.0032 (13)	0.0015 (14)
C59	0.0161 (18)	0.0151 (16)	0.0173 (17)	−0.0013 (14)	−0.0080 (14)	0.0015 (13)
O60	0.0177 (13)	0.0438 (16)	0.0249 (14)	−0.0102 (12)	−0.0071 (11)	0.0223 (12)
C61	0.0201 (18)	0.0226 (17)	0.0156 (17)	−0.0109 (14)	−0.0091 (14)	0.0079 (13)
C62	0.025 (2)	0.031 (2)	0.0137 (16)	−0.0114 (17)	−0.0048 (14)	0.0008 (14)
C63	0.024 (2)	0.0226 (19)	0.031 (2)	−0.0078 (16)	−0.0043 (16)	0.0005 (16)
C64	0.027 (2)	0.033 (2)	0.029 (2)	−0.0091 (18)	−0.0138 (18)	0.0138 (18)
C65	0.030 (2)	0.043 (2)	0.0160 (18)	−0.0106 (18)	−0.0084 (16)	0.0090 (16)
C66	0.0216 (19)	0.0272 (18)	0.0163 (18)	−0.0079 (15)	−0.0045 (15)	0.0010 (14)
C67	0.0251 (7)	0.0248 (7)	0.0238 (7)	−0.0059 (6)	−0.0120 (6)	−0.0063 (6)
C68	0.0243 (9)	0.0246 (9)	0.0246 (9)	−0.0068 (8)	−0.0098 (8)	−0.0023 (8)
C69	0.0244 (10)	0.0271 (9)	0.0258 (9)	−0.0088 (8)	−0.0103 (8)	−0.0027 (8)
C70	0.0258 (10)	0.0308 (10)	0.0226 (9)	−0.0093 (8)	−0.0117 (8)	−0.0053 (8)
C71	0.0265 (10)	0.0345 (10)	0.0254 (9)	−0.0099 (8)	−0.0082 (8)	−0.0061 (8)
C72	0.0256 (9)	0.0316 (9)	0.0262 (8)	−0.0092 (8)	−0.0088 (7)	−0.0068 (8)
I73	0.02995 (14)	0.02291 (11)	0.02524 (13)	−0.00066 (9)	−0.01539 (10)	−0.00772 (9)
C74	0.0269 (7)	0.0339 (7)	0.0263 (7)	−0.0010 (7)	−0.0121 (6)	−0.0107 (7)
C75	0.0252 (9)	0.0307 (9)	0.0253 (9)	−0.0005 (8)	−0.0106 (8)	−0.0065 (8)
C76	0.0252 (10)	0.0312 (10)	0.0255 (9)	0.0004 (9)	−0.0117 (8)	−0.0059 (9)
C77	0.0277 (10)	0.0346 (10)	0.0209 (9)	0.0049 (9)	−0.0122 (8)	−0.0054 (9)
C78	0.0315 (10)	0.0341 (10)	0.0237 (9)	0.0014 (9)	−0.0084 (8)	−0.0070 (9)
C79	0.0288 (9)	0.0343 (9)	0.0271 (9)	−0.0013 (8)	−0.0091 (8)	−0.0090 (8)
I80	0.03165 (15)	0.04183 (16)	0.03126 (16)	0.00053 (12)	−0.01593 (12)	−0.01534 (13)

Geometric parameters (Å, º)

C1—C2	1.321 (6)	C40—C41	1.531 (5)
C1—H11	0.944	C40—H402	0.977
C1—H12	0.941	C40—H401	0.983
C2—C3	1.497 (5)	C41—C42	1.535 (5)
C2—H21	0.935	C41—H411	0.972
C3—O4	1.234 (5)	C41—H412	0.963
C3—N5	1.350 (5)	C42—C43	1.520 (5)
N5—C6	1.474 (4)	C42—N44	1.467 (4)
N5—C10	1.464 (4)	C42—H421	0.974
C6—C7	1.524 (4)	C43—H431	0.964
C6—H61	0.973	C43—H432	0.970
C6—H62	0.970	N44—C45	1.352 (5)
C7—C8	1.533 (4)	N44—N53	1.364 (4)
C7—H72	0.973	C45—N46	1.355 (5)
C7—H71	0.961	C45—C51	1.399 (5)
C8—C9	1.521 (5)	N46—C47	1.327 (5)
C8—H81	0.978	C47—N48	1.345 (5)
C8—H82	0.966	C47—H471	0.940
C9—C10	1.532 (5)	N48—C49	1.368 (5)
C9—N11	1.462 (4)	C49—N50	1.334 (5)
C9—H91	0.983	C49—C51	1.415 (5)
C10—H101	0.967	N50—H501	0.857 (19)
C10—H102	0.977	N50—H502	0.842 (19)
N11—C12	1.352 (5)	C51—C52	1.424 (5)
N11—N20	1.379 (4)	C52—N53	1.332 (5)
C12—N13	1.356 (5)	C52—C54	1.468 (5)
C12—C18	1.412 (5)	C54—C55	1.406 (5)
N13—C14	1.319 (5)	C54—C59	1.396 (6)
C14—N15	1.350 (5)	C55—C56	1.385 (5)
C14—H141	0.933	C55—H551	0.968
N15—C16	1.351 (5)	C56—C57	1.384 (6)
C16—N17	1.332 (5)	C56—H561	0.948
C16—C18	1.409 (5)	C57—C58	1.392 (5)
N17—H172	0.835 (19)	C57—O60	1.381 (4)
N17—H171	0.851 (19)	C58—C59	1.387 (5)
C18—C19	1.431 (5)	C58—H581	0.924
C19—N20	1.326 (5)	C59—H591	0.938
C19—C21	1.483 (5)	O60—C61	1.399 (4)
C21—C22	1.401 (6)	C61—C62	1.382 (5)
C21—C26	1.382 (5)	C61—C66	1.371 (5)
C22—C23	1.380 (5)	C62—C63	1.383 (6)
C22—H221	0.939	C62—H621	0.934
C23—C24	1.387 (5)	C63—C64	1.389 (7)
C23—H231	0.934	C63—H631	0.928
C24—C25	1.382 (6)	C64—C65	1.373 (7)
C24—O27	1.380 (4)	C64—H641	0.911
C25—C26	1.398 (5)	C65—C66	1.392 (5)
C25—H251	0.916	C65—H651	0.939
C26—H261	0.918	C66—H661	0.943
O27—C28	1.401 (4)	C67—C68	1.369 (7)
C28—C29	1.379 (6)	C67—C72	1.377 (6)
C28—C33	1.370 (6)	C67—I73	2.105 (4)
C29—C30	1.394 (6)	C68—C69	1.395 (6)
C29—H291	0.932	C68—H681	0.935
C30—C31	1.390 (7)	C69—C70	1.397 (6)
C30—H301	0.932	C69—H691	0.951
C31—C32	1.377 (7)	C70—C71	1.404 (6)
C31—H311	0.938	C70—H701	0.914
C32—C33	1.401 (6)	C71—C72	1.394 (6)
C32—H321	0.935	C71—H711	0.936
C33—H331	0.932	C72—H721	0.926
C34—C35	1.284 (7)	C74—C75	1.388 (8)
C34—H341	0.937	C74—C79	1.391 (7)
C34—H342	0.942	C74—I80	2.112 (5)
C35—C36	1.503 (5)	C75—C76	1.402 (6)
C35—H351	0.919	C75—H751	0.943
C36—O37	1.222 (5)	C76—C77	1.421 (7)
C36—N38	1.370 (5)	C76—H761	0.925
N38—C39	1.471 (4)	C77—C78	1.262 (7)
N38—C43	1.465 (4)	C77—H771	0.902
C39—C40	1.497 (5)	C78—C79	1.413 (6)
C39—H392	0.964	C78—H781	0.918
C39—H391	0.982	C79—H791	0.945
C2—C1—H11	120.3	C39—C40—C41	111.1 (3)
C2—C1—H12	119.4	C39—C40—H402	110.4
H11—C1—H12	120.3	C41—C40—H402	109.1
C1—C2—C3	121.5 (4)	C39—C40—H401	107.9
C1—C2—H21	119.8	C41—C40—H401	106.9
C3—C2—H21	118.7	H402—C40—H401	111.3
C2—C3—O4	120.5 (4)	C40—C41—C42	110.2 (3)
C2—C3—N5	117.2 (3)	C40—C41—H411	110.6
O4—C3—N5	122.4 (3)	C42—C41—H411	108.5
C3—N5—C6	127.2 (3)	C40—C41—H412	107.4
C3—N5—C10	120.5 (3)	C42—C41—H412	109.4
C6—N5—C10	112.2 (3)	H411—C41—H412	110.7
N5—C6—C7	109.3 (3)	C41—C42—C43	111.6 (3)
N5—C6—H61	111.5	C41—C42—N44	110.5 (3)
C7—C6—H61	110.3	C43—C42—N44	109.1 (3)
N5—C6—H62	107.3	C41—C42—H421	108.9
C7—C6—H62	110.0	C43—C42—H421	108.2
H61—C6—H62	108.3	N44—C42—H421	108.5
C6—C7—C8	110.5 (3)	C42—C43—N38	110.1 (3)
C6—C7—H72	107.4	C42—C43—H431	110.9
C8—C7—H72	108.4	N38—C43—H431	109.5
C6—C7—H71	110.4	C42—C43—H432	109.9
C8—C7—H71	110.7	N38—C43—H432	108.0
H72—C7—H71	109.4	H431—C43—H432	108.5
C7—C8—C9	109.7 (3)	C42—N44—C45	129.1 (3)
C7—C8—H81	109.3	C42—N44—N53	119.5 (3)
C9—C8—H81	108.8	C45—N44—N53	111.1 (3)
C7—C8—H82	109.7	N44—C45—N46	125.6 (3)
C9—C8—H82	109.0	N44—C45—C51	107.3 (3)
H81—C8—H82	110.3	N46—C45—C51	127.0 (3)
C8—C9—C10	112.5 (3)	C45—N46—C47	110.9 (3)
C8—C9—N11	111.9 (3)	N46—C47—N48	129.4 (3)
C10—C9—N11	108.9 (3)	N46—C47—H471	115.1
C8—C9—H91	107.9	N48—C47—H471	115.5
C10—C9—H91	108.0	C47—N48—C49	118.3 (3)
N11—C9—H91	107.5	N48—C49—N50	116.4 (3)
C9—C10—N5	109.6 (3)	N48—C49—C51	117.9 (3)
C9—C10—H101	108.8	N50—C49—C51	125.7 (3)
N5—C10—H101	109.2	C49—N50—H501	117.9 (17)
C9—C10—H102	109.5	C49—N50—H502	119.1 (17)
N5—C10—H102	110.2	H501—N50—H502	123 (2)
H101—C10—H102	109.6	C49—C51—C45	116.0 (3)
C9—N11—C12	132.0 (3)	C49—C51—C52	139.2 (3)
C9—N11—N20	116.9 (3)	C45—C51—C52	104.7 (3)
C12—N11—N20	111.1 (3)	C51—C52—N53	110.1 (3)
N11—C12—N13	126.8 (3)	C51—C52—C54	131.7 (3)
N11—C12—C18	107.3 (3)	N53—C52—C54	118.0 (3)
N13—C12—C18	125.9 (3)	N44—N53—C52	106.8 (3)
C12—N13—C14	111.2 (3)	C52—C54—C55	121.1 (4)
N13—C14—N15	129.8 (3)	C52—C54—C59	120.1 (4)
N13—C14—H141	114.5	C55—C54—C59	118.6 (4)
N15—C14—H141	115.7	C54—C55—C56	120.9 (4)
C14—N15—C16	118.1 (3)	C54—C55—H551	119.0
N15—C16—N17	116.7 (3)	C56—C55—H551	120.1
N15—C16—C18	118.6 (3)	C55—C56—C57	119.3 (4)
N17—C16—C18	124.8 (4)	C55—C56—H561	119.3
C16—N17—H172	120.0 (17)	C57—C56—H561	121.4
C16—N17—H171	120.6 (17)	C56—C57—C58	120.9 (3)
H172—N17—H171	115 (3)	C56—C57—O60	122.5 (3)
C12—C18—C16	116.3 (3)	C58—C57—O60	116.5 (3)
C12—C18—C19	104.2 (3)	C57—C58—C59	119.7 (4)
C16—C18—C19	139.2 (3)	C57—C58—H581	119.3
C18—C19—N20	110.8 (3)	C59—C58—H581	121.0
C18—C19—C21	130.8 (3)	C54—C59—C58	120.6 (4)
N20—C19—C21	118.5 (3)	C54—C59—H591	118.5
N11—N20—C19	106.6 (3)	C58—C59—H591	120.9
C19—C21—C22	118.5 (3)	C57—O60—C61	118.9 (3)
C19—C21—C26	122.3 (4)	O60—C61—C62	121.0 (3)
C22—C21—C26	119.1 (3)	O60—C61—C66	117.2 (4)
C21—C22—C23	120.6 (4)	C62—C61—C66	121.6 (3)
C21—C22—H221	120.8	C61—C62—C63	119.3 (4)
C23—C22—H221	118.6	C61—C62—H621	119.8
C22—C23—C24	119.4 (4)	C63—C62—H621	120.9
C22—C23—H231	120.1	C62—C63—C64	119.4 (4)
C24—C23—H231	120.5	C62—C63—H631	119.8
C23—C24—C25	121.2 (3)	C64—C63—H631	120.9
C23—C24—O27	114.8 (3)	C63—C64—C65	120.8 (4)
C25—C24—O27	124.0 (3)	C63—C64—H641	119.0
C24—C25—C26	118.9 (3)	C65—C64—H641	120.1
C24—C25—H251	119.4	C64—C65—C66	119.9 (4)
C26—C25—H251	121.7	C64—C65—H651	119.4
C25—C26—C21	120.8 (4)	C66—C65—H651	120.7
C25—C26—H261	120.5	C65—C66—C61	119.0 (4)
C21—C26—H261	118.7	C65—C66—H661	121.9
C24—O27—C28	118.4 (3)	C61—C66—H661	119.1
O27—C28—C29	118.4 (4)	C68—C67—C72	121.7 (4)
O27—C28—C33	118.9 (4)	C68—C67—I73	118.5 (3)
C29—C28—C33	122.5 (4)	C72—C67—I73	119.9 (3)
C28—C29—C30	118.4 (4)	C67—C68—C69	119.4 (4)
C28—C29—H291	120.1	C67—C68—H681	120.0
C30—C29—H291	121.5	C69—C68—H681	120.6
C29—C30—C31	120.1 (4)	C68—C69—C70	120.6 (4)
C29—C30—H301	119.2	C68—C69—H691	119.7
C31—C30—H301	120.7	C70—C69—H691	119.7
C30—C31—C32	120.1 (4)	C69—C70—C71	118.4 (4)
C30—C31—H311	120.8	C69—C70—H701	121.0
C32—C31—H311	119.0	C71—C70—H701	120.5
C31—C32—C33	120.2 (4)	C70—C71—C72	120.6 (4)
C31—C32—H321	120.6	C70—C71—H711	118.2
C33—C32—H321	119.2	C72—C71—H711	121.2
C32—C33—C28	118.5 (4)	C71—C72—C67	119.1 (4)
C32—C33—H331	121.1	C71—C72—H721	119.8
C28—C33—H331	120.4	C67—C72—H721	121.1
C35—C34—H341	120.8	C75—C74—C79	122.2 (5)
C35—C34—H342	121.2	C75—C74—I80	117.8 (4)
H341—C34—H342	117.9	C79—C74—I80	119.9 (4)
C34—C35—C36	121.9 (4)	C74—C75—C76	117.7 (5)
C34—C35—H351	118.9	C74—C75—H751	121.7
C36—C35—H351	119.2	C76—C75—H751	120.6
C35—C36—O37	121.4 (4)	C75—C76—C77	118.0 (5)
C35—C36—N38	116.4 (3)	C75—C76—H761	120.4
O37—C36—N38	122.1 (3)	C77—C76—H761	121.7
C36—N38—C39	122.5 (3)	C76—C77—C78	123.2 (4)
C36—N38—C43	118.0 (3)	C76—C77—H771	118.4
C39—N38—C43	114.0 (3)	C78—C77—H771	118.4
N38—C39—C40	111.1 (3)	C77—C78—C79	121.7 (4)
N38—C39—H392	110.4	C77—C78—H781	120.3
C40—C39—H392	108.8	C79—C78—H781	118.0
N38—C39—H391	107.7	C78—C79—C74	117.2 (5)
C40—C39—H391	108.6	C78—C79—H791	121.9
H392—C39—H391	110.1	C74—C79—H791	120.9

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C8—H82···N13	0.97	2.53	3.187 (6)	126 (1)
C68—H681···N53	0.94	2.56	3.440 (6)	158 (1)
C70—H701···O37^i	0.91	2.38	3.266 (6)	165 (1)
C75—H751···N20	0.94	2.39	3.251 (6)	152 (1)
N17—H172···O37	0.84	2.37	3.017 (6)	134 (2)
N50—H501···N15^ii	0.86	2.12	2.977 (6)	175 (4)
N50—H502···O4	0.84	2.32	2.953 (6)	132 (2)
N17—H171···N48^iii	0.85	2.11	2.941 (6)	167 (4)

Symmetry codes: (i) x, y, z+1; (ii) x+1, y, z; (iii) x−1, y, z.

(chloro)

Crystal data

C56H53ClN12O4	γ = 79.3096 (9)°
Mr = 993.6	V = 1289.11 (4) Å^3
Triclinic, P1	Z = 1
Hall symbol: P 1	F(000) = 522
a = 14.0474 (3) Å	Dx = 1.280 Mg m^−3
b = 10.21941 (15) Å	Cu Kα radiation, λ = 1.54059 Å
c = 10.37318 (18) Å	µ = 1.11 mm^−1
α = 116.4028 (10)°	T = 293 K
β = 85.6175 (14)°	white

Data collection

Empyrean of PANalytical diffractometer	Data collection mode: transmission
Radiation source: Sealed Cu X-ray tube	Scan method: continuous
None monochromator	2θmin = 4.556°, 2θmax = 79.989°, 2θstep = 0.013°
Specimen mounting: capillary

Refinement

Rp = 0.018	193 restraints
Rwp = 0.024	287 constraints
Rexp = 0.007	H-atom parameters constrained
R(F) = 0.057	Weighting scheme based on measured s.u.'s
5864 data points	(Δ/σ)max = 0.043
Excluded region(s): from 3.007 to 4.547	Background function: 30 Legendre polynoms
Profile function: Pseudo-Voigt	Preferred orientation correction: none
268 parameters

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
O1	−0.1405 (12)	0.6649 (11)	0.5843 (14)	0.0620 (15)*
C2	−0.1486 (7)	0.7744 (11)	0.5608 (10)	0.0620 (15)*
N3	−0.1387 (7)	0.9082 (10)	0.6633 (9)	0.0620 (15)*
C4	−0.1770 (11)	0.7651 (16)	0.4224 (10)	0.0620 (15)*
C5	−0.0945 (6)	0.9184 (11)	0.7881 (8)	0.0620 (15)*
C6	−0.1627 (7)	1.0538 (10)	0.6597 (10)	0.0620 (15)*
C7	−0.2601 (10)	0.736 (5)	0.3854 (16)	0.0620 (15)*
C8	−0.0012 (5)	0.9724 (7)	0.7890 (6)	0.0620 (15)*
C9	−0.0696 (10)	1.1115 (12)	0.6577 (12)	0.0620 (15)*
N10	0.0434 (5)	0.9763 (7)	0.9128 (6)	0.0620 (15)*
C11	−0.0186 (9)	1.1210 (10)	0.7861 (13)	0.0620 (15)*
N12	0.1307 (7)	0.8724 (10)	0.8830 (7)	0.0620 (15)*
C13	0.0207 (5)	1.0757 (11)	1.0565 (6)	0.0620 (15)*
C14	0.1651 (5)	0.9128 (8)	1.0075 (7)	0.0620 (15)*
C15	0.0959 (5)	1.0395 (9)	1.1235 (6)	0.0620 (15)*
N16	−0.0636 (8)	1.1884 (17)	1.1246 (8)	0.0620 (15)*
C17	0.2586 (6)	0.8186 (7)	1.0068 (10)	0.0620 (15)*
C18	0.0827 (7)	1.1252 (14)	1.2790 (6)	0.0620 (15)*
C19	−0.0647 (8)	1.2613 (13)	1.2668 (8)	0.0620 (15)*
C20	0.3263 (7)	0.8769 (9)	1.0911 (14)	0.0620 (15)*
C21	0.2817 (9)	0.6635 (8)	0.9098 (17)	0.0620 (15)*
N22	−0.0014 (11)	1.2371 (18)	1.3473 (7)	0.0620 (15)*
N23	0.1430 (16)	1.101 (3)	1.3618 (8)	0.0620 (15)*
C24	0.4184 (7)	0.7862 (9)	1.0755 (17)	0.0620 (15)*
C25	0.3693 (8)	0.5726 (7)	0.9001 (18)	0.0620 (15)*
C26	0.4375 (6)	0.6324 (8)	0.9790 (12)	0.0620 (15)*
O27	0.5282 (6)	0.5294 (11)	0.9456 (9)	0.0620 (15)*
C28	0.5637 (5)	0.5053 (11)	1.0574 (9)	0.0620 (15)*
C29	0.6540 (10)	0.399 (2)	1.0139 (16)	0.0620 (15)*
C30	0.5075 (9)	0.5662 (18)	1.1889 (10)	0.0620 (15)*
C31	0.6888 (13)	0.363 (2)	1.1163 (19)	0.0620 (15)*
C32	0.5471 (12)	0.531 (2)	1.2992 (12)	0.0620 (15)*
C33	0.6336 (14)	0.431 (2)	1.2561 (17)	0.0620 (15)*
O1a	1.2817 (11)	0.8826 (15)	0.4235 (17)	0.0620 (15)*
C2a	1.2724 (8)	0.8012 (11)	0.4806 (11)	0.0620 (15)*
N3a	1.2044 (6)	0.7192 (9)	0.4499 (7)	0.0620 (15)*
C4a	1.3387 (10)	0.7866 (19)	0.5807 (15)	0.0620 (15)*
C5a	1.1473 (6)	0.7124 (7)	0.3376 (7)	0.0620 (15)*
C6a	1.1856 (8)	0.6185 (16)	0.5108 (9)	0.0620 (15)*
C7a	1.3893 (12)	0.886 (2)	0.6442 (14)	0.0620 (15)*
C8a	1.1693 (4)	0.5530 (6)	0.2124 (7)	0.0620 (15)*
C9a	1.2098 (11)	0.4552 (14)	0.3887 (15)	0.0620 (15)*
N10a	1.1125 (4)	0.5505 (6)	0.0995 (6)	0.0620 (15)*
C11a	1.1531 (10)	0.4405 (11)	0.2641 (13)	0.0620 (15)*
N12a	1.0270 (8)	0.6614 (13)	0.1414 (8)	0.0620 (15)*
C13a	1.1228 (6)	0.4486 (8)	−0.0421 (6)	0.0620 (15)*
C14a	0.9861 (4)	0.6315 (8)	0.0227 (8)	0.0620 (15)*
C15a	1.0468 (5)	0.4995 (8)	−0.0996 (6)	0.0620 (15)*
N16a	1.1979 (10)	0.3220 (14)	−0.1175 (9)	0.0620 (15)*
C17a	0.8879 (5)	0.7270 (7)	0.0393 (11)	0.0620 (15)*
C18a	1.0523 (7)	0.4199 (12)	−0.2542 (6)	0.0620 (15)*
C19a	1.1915 (14)	0.2550 (18)	−0.2578 (9)	0.0620 (15)*
C20a	0.8674 (7)	0.8818 (8)	0.104 (2)	0.0620 (15)*
C21a	0.8119 (6)	0.6554 (8)	−0.0116 (18)	0.0620 (15)*
N22a	1.1267 (13)	0.2928 (19)	−0.3298 (8)	0.0620 (15)*
N23a	0.9959 (17)	0.464 (2)	−0.3302 (9)	0.0620 (15)*
C24a	0.7726 (8)	0.9677 (8)	0.122 (2)	0.0620 (15)*
C25a	0.7209 (6)	0.7380 (10)	−0.0010 (18)	0.0620 (15)*
C26a	0.7001 (5)	0.8915 (10)	0.0691 (14)	0.0620 (15)*
O27a	0.6002 (5)	0.9620 (14)	0.0921 (13)	0.0620 (15)*
C28a	0.5689 (6)	1.0211 (12)	−0.0005 (12)	0.0620 (15)*
C29a	0.4771 (11)	1.125 (3)	0.053 (2)	0.0620 (15)*
C30a	0.6296 (9)	0.992 (2)	−0.1201 (14)	0.0620 (15)*
C31a	0.4461 (13)	1.195 (2)	−0.028 (2)	0.0620 (15)*
C32a	0.5942 (13)	1.063 (3)	−0.2086 (19)	0.0620 (15)*
C33a	0.5054 (16)	1.158 (2)	−0.1581 (19)	0.0620 (15)*
H1c4	−0.1328	0.780935	0.358455	0.0744*
H1c5	−0.079571	0.821241	0.784683	0.0744*
H2c5	−0.14052	0.986983	0.876672	0.0744*
H1c6	−0.210667	1.126313	0.744528	0.0744*
H2c6	−0.189813	1.040374	0.573674	0.0744*
H1c7	−0.309661	0.736372	0.454789	0.0744*
H2c7	−0.271943	0.714245	0.28885	0.0744*
H1c8	0.044497	0.902125	0.700658	0.0744*
H1c9	−0.086681	1.20936	0.662873	0.0744*
H2c9	−0.024826	1.045148	0.567157	0.0744*
H1c11	0.043282	1.145616	0.77568	0.0744*
H2c11	−0.059363	1.198663	0.876215	0.0744*
H1c19	−0.120378	1.345678	1.320828	0.0744*
H1c20	0.309847	0.981706	1.161771	0.0744*
H1c21	0.235496	0.621113	0.849785	0.0744*
H1c24	0.467118	0.828356	1.129577	0.0744*
H1c25	0.382936	0.465902	0.837341	0.0744*
H1c29	0.690063	0.353378	0.915748	0.0744*
H1c30	0.443142	0.631044	1.210531	0.0744*
H1c31	0.750793	0.291433	1.091681	0.0744*
H1c32	0.512284	0.578383	1.398167	0.0744*
H1c33	0.659287	0.404097	1.326545	0.0744*
H1c4a	1.344687	0.701876	0.599582	0.0744*
H1c5a	1.162582	0.778895	0.301104	0.0744*
H2c5a	1.078426	0.74581	0.379098	0.0744*
H1c6a	1.11757	0.648579	0.55596	0.0744*
H2c6a	1.225798	0.625887	0.583333	0.0744*
H1c7a	1.443233	0.893418	0.587064	0.0744*
H2c7a	1.372363	0.951957	0.74771	0.0744*
H1c8a	1.237954	0.52207	0.170185	0.0744*
H1c9a	1.193246	0.391548	0.42812	0.0744*
H2c9a	1.279277	0.421436	0.350886	0.0744*
H1c11a	1.175607	0.340286	0.184124	0.0744*
H2c11a	1.084057	0.458891	0.298249	0.0744*
H1c19a	1.241904	0.164363	−0.317304	0.0744*
H1c20a	0.918865	0.93165	0.137518	0.0744*
H1c21a	0.824404	0.547674	−0.053951	0.0744*
H1c24a	0.757995	1.075831	0.16989	0.0744*
H1c25a	0.67117	0.687845	−0.043061	0.0744*
H1c29a	0.437339	1.146379	0.142576	0.0744*
H1c30a	0.694424	0.926826	−0.147371	0.0744*
H1c31a	0.38405	1.267946	0.004983	0.0744*
H1c32a	0.633232	1.041449	−0.29895	0.0744*
H1c33a	0.480917	1.204656	−0.215603	0.0744*
H1n23	0.19741	1.030562	1.321752	0.0744*
H2n23	0.128482	1.155876	1.456388	0.0744*
H1n23a	0.947732	0.544644	−0.285506	0.0744*
H2n23a	1.006749	0.412593	−0.425217	0.0744*
Cl1a	0.4412 (13)	0.2218 (18)	0.480 (3)	0.106 (9)*	0.721 (14)
C51a	0.5362 (15)	0.311 (2)	0.536 (3)	0.0620 (15)*	0.721 (14)
C52a	0.515 (2)	0.465 (2)	0.602 (5)	0.0620 (15)*	0.721 (14)
C53a	0.590 (2)	0.536 (3)	0.632 (5)	0.0620 (15)*	0.721 (14)
C54a	0.686 (2)	0.455 (4)	0.606 (7)	0.0620 (15)*	0.721 (14)
C55a	0.7045 (18)	0.299 (4)	0.545 (6)	0.0620 (15)*	0.721 (14)
C56a	0.6308 (15)	0.227 (3)	0.507 (5)	0.0620 (15)*	0.721 (14)
H1c52a	0.447794	0.522447	0.628205	0.0744*	0.721 (14)
H1c53a	0.576427	0.643018	0.670783	0.0744*	0.721 (14)
H1c54a	0.738026	0.504927	0.629071	0.0744*	0.721 (14)
H1c55a	0.77053	0.241834	0.528534	0.0744*	0.721 (14)
H1c56a	0.644864	0.118642	0.461212	0.0744*	0.721 (14)
Cl1b	0.755 (4)	0.412 (8)	0.593 (9)	0.106 (9)*	0.279 (14)
C51b	0.661 (3)	0.318 (6)	0.551 (7)	0.0620 (15)*	0.279 (14)
C52b	0.686 (5)	0.164 (7)	0.479 (9)	0.0620 (15)*	0.279 (14)
C53b	0.614 (7)	0.090 (8)	0.431 (9)	0.0620 (15)*	0.279 (14)
C54b	0.517 (5)	0.167 (9)	0.463 (12)	0.0620 (15)*	0.279 (14)
C55b	0.493 (4)	0.322 (9)	0.543 (12)	0.0620 (15)*	0.279 (14)
C56b	0.565 (4)	0.399 (7)	0.585 (9)	0.0620 (15)*	0.279 (14)
H1c52b	0.752557	0.109408	0.462972	0.0744*	0.279 (14)
H1c53b	0.631484	−0.018063	0.373148	0.0744*	0.279 (14)
H1c54b	0.466545	0.113766	0.432051	0.0744*	0.279 (14)
H1c55b	0.425771	0.377391	0.568822	0.0744*	0.279 (14)
H1c56b	0.548407	0.507103	0.63604	0.0744*	0.279 (14)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
?	?	?	?	?	?	?

Geometric parameters (Å, º)

O1—C2	1.234 (19)	C4a—H1c4a	0.96
C2—N3	1.350 (13)	C5a—C8a	1.519 (7)
C2—C4	1.487 (17)	C5a—H1c5a	0.96
N3—C5	1.448 (14)	C5a—H2c5a	0.96
N3—C6	1.481 (16)	C6a—C9a	1.533 (16)
C4—C7	1.30 (2)	C6a—H1c6a	0.96
C4—H1c4	0.96	C6a—H2c6a	0.96
C5—C8	1.513 (13)	C7a—H1c7a	0.96
C5—H1c5	0.96	C7a—H2c7a	0.96
C5—H2c5	0.96	C8a—N10a	1.460 (10)
C6—C9	1.535 (18)	C8a—C11a	1.513 (17)
C6—H1c6	0.96	C8a—H1c8a	0.96
C6—H2c6	0.96	C9a—C11a	1.54 (2)
C7—H1c7	0.96	C9a—H1c9a	0.96
C7—H2c7	0.96	C9a—H2c9a	0.96
C8—N10	1.460 (10)	N10a—N12a	1.376 (11)
C8—C11	1.507 (15)	N10a—C13a	1.347 (7)
C8—H1c8	0.96	C11a—H1c11a	0.96
C9—C11	1.533 (19)	C11a—H2c11a	0.96
C9—H1c9	0.96	N12a—C14a	1.332 (12)
C9—H2c9	0.96	C13a—C15a	1.390 (11)
N10—N12	1.376 (11)	C13a—N16a	1.367 (13)
N10—C13	1.348 (7)	C14a—C15a	1.429 (7)
C11—H1c11	0.96	C14a—C17a	1.483 (9)
C11—H2c11	0.96	C15a—C18a	1.427 (8)
N12—C14	1.330 (11)	N16a—C19a	1.324 (13)
C13—C15	1.390 (11)	C17a—C20a	1.376 (10)
C13—N16	1.367 (13)	C17a—C21a	1.409 (12)
C14—C15	1.428 (8)	C18a—N22a	1.363 (17)
C14—C17	1.475 (11)	C18a—N23a	1.32 (2)
C15—C18	1.428 (8)	C19a—N22a	1.33 (2)
N16—C19	1.322 (10)	C19a—H1c19a	0.96
C17—C20	1.378 (14)	C20a—C24a	1.400 (15)
C17—C21	1.404 (9)	C20a—H1c20a	0.96
C18—N22	1.362 (16)	C21a—C25a	1.362 (13)
C18—N23	1.32 (2)	C21a—H1c21a	0.96
C19—N22	1.328 (17)	N23a—H1n23a	0.87
C19—H1c19	0.96	N23a—H2n23a	0.87
C20—C24	1.396 (14)	C24a—C26a	1.396 (14)
C20—H1c20	0.96	C24a—H1c24a	0.96
C21—C25	1.365 (16)	C25a—C26a	1.363 (13)
C21—H1c21	0.96	C25a—H1c25a	0.96
N23—H1n23	0.87	C26a—O27a	1.401 (11)
N23—H2n23	0.87	O27a—C28a	1.40 (2)
C24—C26	1.396 (11)	C28a—C29a	1.398 (18)
C24—H1c24	0.96	C28a—C30a	1.331 (18)
C25—C26	1.361 (16)	C29a—C31a	1.37 (4)
C25—H1c25	0.96	C29a—H1c29a	0.96
C26—O27	1.401 (11)	C30a—C32a	1.46 (3)
O27—C28	1.397 (15)	C30a—H1c30a	0.96
C28—C29	1.398 (17)	C31a—C33a	1.39 (3)
C28—C30	1.330 (13)	C31a—H1c31a	0.96
C29—C31	1.37 (3)	C32a—C33a	1.33 (3)
C29—H1c29	0.96	C32a—H1c32a	0.96
C30—C32	1.46 (2)	C33a—H1c33a	0.96
C30—H1c30	0.96	C51a—C52a	1.36 (3)
C31—C33	1.39 (2)	C51a—C56a	1.37 (3)
C31—H1c31	0.96	C52a—C53a	1.37 (5)
C32—C33	1.33 (2)	C52a—H1c52a	0.96
C32—H1c32	0.96	C53a—C54a	1.37 (5)
C33—H1c33	0.96	C53a—H1c53a	0.96
O1a—C2a	1.23 (2)	C54a—C55a	1.38 (5)
C2a—N3a	1.350 (15)	C54a—H1c54a	0.96
C2a—C4a	1.48 (2)	C55a—C56a	1.37 (4)
N3a—C5a	1.447 (11)	C55a—H1c55a	0.96
N3a—C6a	1.48 (2)	C56a—H1c56a	0.96
C4a—C7a	1.31 (3)
O1—C2—N3	121.2 (12)	C7a—C4a—H1c4a	119.08
O1—C2—C4	120.5 (11)	N3a—C5a—C8a	110.9 (6)
N3—C2—C4	118.1 (12)	N3a—C5a—H1c5a	109.47
C2—N3—C5	120.5 (10)	N3a—C5a—H2c5a	109.47
C2—N3—C6	126.6 (10)	C8a—C5a—H1c5a	109.47
C5—N3—C6	112.7 (8)	C8a—C5a—H2c5a	109.47
C2—C4—C7	121.8 (18)	H1c5a—C5a—H2c5a	107.97
C2—C4—H1c4	119.09	N3a—C6a—C9a	110.1 (9)
C7—C4—H1c4	119.09	N3a—C6a—H1c6a	109.47
N3—C5—C8	110.9 (9)	N3a—C6a—H2c6a	109.47
N3—C5—H1c5	109.47	C9a—C6a—H1c6a	109.47
N3—C5—H2c5	109.47	C9a—C6a—H2c6a	109.47
C8—C5—H1c5	109.47	H1c6a—C6a—H2c6a	108.88
C8—C5—H2c5	109.47	C4a—C7a—H1c7a	120
H1c5—C5—H2c5	107.98	C4a—C7a—H2c7a	120
N3—C6—C9	110.1 (9)	H1c7a—C7a—H2c7a	120
N3—C6—H1c6	109.47	C5a—C8a—N10a	109.7 (5)
N3—C6—H2c6	109.47	C5a—C8a—C11a	112.2 (7)
C9—C6—H1c6	109.47	C5a—C8a—H1c8a	108.64
C9—C6—H2c6	109.47	N10a—C8a—C11a	112.7 (7)
H1c6—C6—H2c6	108.86	N10a—C8a—H1c8a	108.1
C4—C7—H1c7	120	C11a—C8a—H1c8a	105.33
C4—C7—H2c7	120	C6a—C9a—C11a	111.2 (11)
H1c7—C7—H2c7	120	C6a—C9a—H1c9a	109.47
C5—C8—N10	109.7 (7)	C6a—C9a—H2c9a	109.47
C5—C8—C11	112.2 (8)	C11a—C9a—H1c9a	109.47
C5—C8—H1c8	108.65	C11a—C9a—H2c9a	109.47
N10—C8—C11	112.7 (7)	H1c9a—C9a—H2c9a	107.66
N10—C8—H1c8	108.08	C8a—N10a—N12a	117.7 (5)
C11—C8—H1c8	105.33	C8a—N10a—C13a	131.5 (5)
C6—C9—C11	111.2 (11)	N12a—N10a—C13a	110.5 (6)
C6—C9—H1c9	109.47	C8a—C11a—C9a	110.1 (10)
C6—C9—H2c9	109.47	C8a—C11a—H1c11a	109.47
C11—C9—H1c9	109.47	C8a—C11a—H2c11a	109.47
C11—C9—H2c9	109.47	C9a—C11a—H1c11a	109.47
H1c9—C9—H2c9	107.66	C9a—C11a—H2c11a	109.47
C8—N10—N12	117.7 (5)	H1c11a—C11a—H2c11a	108.81
C8—N10—C13	131.5 (6)	N10a—N12a—C14a	106.8 (6)
N12—N10—C13	110.5 (6)	N10a—C13a—C15a	107.9 (5)
C8—C11—C9	110.1 (8)	N10a—C13a—N16a	125.7 (8)
C8—C11—H1c11	109.47	C15a—C13a—N16a	126.3 (7)
C8—C11—H2c11	109.47	N12a—C14a—C15a	109.8 (7)
C9—C11—H1c11	109.47	N12a—C14a—C17a	118.3 (7)
C9—C11—H2c11	109.47	C15a—C14a—C17a	131.8 (7)
H1c11—C11—H2c11	108.82	C13a—C15a—C14a	104.7 (5)
N10—N12—C14	106.8 (5)	C13a—C15a—C18a	117.0 (6)
N10—C13—C15	108.0 (6)	C14a—C15a—C18a	138.1 (8)
N10—C13—N16	125.7 (7)	C13a—N16a—C19a	110.3 (12)
C15—C13—N16	126.3 (6)	C14a—C17a—C20a	123.1 (8)
N12—C14—C15	109.8 (7)	C14a—C17a—C21a	118.2 (6)
N12—C14—C17	118.2 (6)	C20a—C17a—C21a	118.7 (7)
C15—C14—C17	131.7 (7)	C15a—C18a—N22a	116.8 (9)
C13—C15—C14	104.8 (5)	C15a—C18a—N23a	125.5 (9)
C13—C15—C18	117.0 (6)	N22a—C18a—N23a	117.6 (8)
C14—C15—C18	138.1 (8)	N16a—C19a—N22a	130.5 (13)
C13—N16—C19	110.3 (10)	N16a—C19a—H1c19a	114.73
C14—C17—C20	123.0 (6)	N22a—C19a—H1c19a	114.73
C14—C17—C21	118.2 (9)	C17a—C20a—C24a	121.1 (9)
C20—C17—C21	118.7 (8)	C17a—C20a—H1c20a	119.44
C15—C18—N22	116.9 (8)	C24a—C20a—H1c20a	119.44
C15—C18—N23	125.5 (10)	C17a—C21a—C25a	120.4 (7)
N22—C18—N23	117.6 (8)	C17a—C21a—H1c21a	119.79
N16—C19—N22	130.6 (10)	C25a—C21a—H1c21a	119.79
N16—C19—H1c19	114.72	C18a—N22a—C19a	118.8 (8)
N22—C19—H1c19	114.72	C18a—N23a—H1n23a	120
C17—C20—C24	121.1 (7)	C18a—N23a—H2n23a	120
C17—C20—H1c20	119.44	H1n23a—N23a—H2n23a	120
C24—C20—H1c20	119.44	C20a—C24a—C26a	118.0 (7)
C17—C21—C25	120.4 (11)	C20a—C24a—H1c24a	121.01
C17—C21—H1c21	119.78	C26a—C24a—H1c24a	121.01
C25—C21—H1c21	119.78	C21a—C25a—C26a	120.3 (9)
C18—N22—C19	118.9 (6)	C21a—C25a—H1c25a	119.83
C18—N23—H1n23	120	C26a—C25a—H1c25a	119.83
C18—N23—H2n23	120	C24a—C26a—C25a	121.2 (8)
H1n23—N23—H2n23	120	C24a—C26a—O27a	124.3 (9)
C20—C24—C26	118.0 (10)	C25a—C26a—O27a	114.3 (9)
C20—C24—H1c24	121.01	C26a—O27a—C28a	118.8 (11)
C26—C24—H1c24	121.01	O27a—C28a—C29a	115.0 (14)
C21—C25—C26	120.4 (7)	O27a—C28a—C30a	120.3 (10)
C21—C25—H1c25	119.82	C29a—C28a—C30a	124.2 (17)
C26—C25—H1c25	119.82	C28a—C29a—C31a	117.5 (18)
C24—C26—C25	121.2 (8)	C28a—C29a—H1c29a	121.26
C24—C26—O27	124.3 (9)	C31a—C29a—H1c29a	121.26
C25—C26—O27	114.3 (7)	C28a—C30a—C32a	117.8 (12)
C26—O27—C28	118.8 (8)	C28a—C30a—H1c30a	121.11
O27—C28—C29	115.0 (10)	C32a—C30a—H1c30a	121.11
O27—C28—C30	120.3 (9)	C29a—C31a—C33a	119.1 (16)
C29—C28—C30	124.1 (13)	C29a—C31a—H1c31a	120.43
C28—C29—C31	117.5 (13)	C33a—C31a—H1c31a	120.43
C28—C29—H1c29	121.26	C30a—C32a—C33a	117.0 (18)
C31—C29—H1c29	121.26	C30a—C32a—H1c32a	121.51
C28—C30—C32	117.8 (11)	C33a—C32a—H1c32a	121.51
C28—C30—H1c30	121.11	C31a—C33a—C32a	124 (2)
C32—C30—H1c30	121.11	C31a—C33a—H1c33a	117.89
C29—C31—C33	119.1 (17)	C32a—C33a—H1c33a	117.89
C29—C31—H1c31	120.43	C52a—C51a—C56a	121 (2)
C33—C31—H1c31	120.43	C51a—C52a—C53a	119 (2)
C30—C32—C33	117.0 (12)	C51a—C52a—H1c52a	120.43
C30—C32—H1c32	121.52	C53a—C52a—H1c52a	120.43
C33—C32—H1c32	121.52	C52a—C53a—C54a	121 (3)
C31—C33—C32	124 (2)	C52a—C53a—H1c53a	119.57
C31—C33—H1c33	117.89	C54a—C53a—H1c53a	119.57
C32—C33—H1c33	117.89	C53a—C54a—C55a	119 (3)
O1a—C2a—N3a	121.2 (13)	C53a—C54a—H1c54a	120.69
O1a—C2a—C4a	120.6 (14)	C55a—C54a—H1c54a	120.69
N3a—C2a—C4a	118.2 (13)	C54a—C55a—C56a	121 (3)
C2a—N3a—C5a	120.5 (10)	C54a—C55a—H1c55a	119.43
C2a—N3a—C6a	126.6 (9)	C56a—C55a—H1c55a	119.43
C5a—N3a—C6a	112.7 (8)	C51a—C56a—C55a	119 (3)
C2a—C4a—C7a	121.8 (19)	C51a—C56a—H1c56a	120.67
C2a—C4a—H1c4a	119.08	C55a—C56a—H1c56a	120.67